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Sample records for phosphodiesterase iii inhibitor

  1. Inhibitors of cyclic nucleotide phosphodiesterase isozymes type-III and type-IV suppress mitogenesis of rat mesangial cells.

    PubMed Central

    Matousovic, K; Grande, J P; Chini, C C; Chini, E N; Dousa, T P

    1995-01-01

    We studied interactions between the mitogen-activated protein kinase (MAPK) signalling pathway and cAMP-protein kinase (PKA) signaling pathway in regulation of mitogenesis of mesangial cells (MC) determined by [3H]thymidine incorporation, with or without added EGF. Forskolin or dibutyryl cAMP strongly (by 60-70%) inhibited [3H]thymidine incorporation into MC. Cilostamide, lixazinone or cilostazol selective inhibitors of cAMP-phosphodiesterase (PDE) isozyme PDE-III, inhibited mitogenesis to similar extent as forskolin and DBcAMP and activated in situ PKA, but without detectable increase in cAMP levels. Cilostamide and cilostazol were more than three times more effective at inhibiting mesangial mitogenesis than rolipram and denbufylline, inhibitors of isozyme PDE-IV, even though PDE-IV was two times more abundant in MC than was PDE-III. On the other hand, when incubated with forskolin, rolipram-enhanced cAMP accumulation was far greater (10-100x) than with cilostamide. EGF increased MAPK activity (+300%); PDE isozyme inhibitors which suppressed mitogenesis also inhibited MAPK. PDE isozyme inhibitors also suppressed PDGF-stimulated MC proliferation. We conclude that cAMP inhibits the mitogen-dependent MAPK-signaling pathway probably by decreasing the activity of Raf-1 due to PKA-catalyzed phosphorylation. Further, we surmise that minor increase in the cAMP pool metabolized by PDE-III is intimately related to regulation of mesangial proliferation. Thus, PDE isozyme inhibitors have the potential to suppress MC proliferation by a focused effect upon signaling pathways. Images PMID:7615811

  2. Pharmacology of phosphodiesterase-5 inhibitors.

    PubMed

    Corbin, J D; Francis, S H

    2002-01-01

    The clinical properties (efficacy and safety profile) of a medicine are related not only to its mode of action, but also to its selectivity for its target (usually a receptor or enzyme) and are also influenced by its pharmacokinetic properties (absorption, distribution, metabolism and elimination). The growing number of phosphodiesterase inhibitors that are selective for phosphodiesterase-5 (PDE5) represent a promising new class of compounds that are useful for the treatment of erectile dysfunction and perhaps other disorders. Some of the basic pharmacodynamic and pharmacokinetic parameters that describe drug action are discussed with regard to the new PDE5 inhibitors. Central topics reviewed are the concentration that produces a given in vitro response, or potency (IC50), maximum plasma concentration (Cmax), time to Cmax (Tmax), half-life (t 1/2), area under the curve (AUC), bioavailability, onset and duration of action, and the balance to achieve optimum safety and efficacy. To illustrate these concepts, a group of inhibitors with varying selectivities and potencies for PDE5 (theophylline, IBMX, zaprinast, sildenafil, tadalafil and vardenafil) are discussed. Each drug has its own set of unique pharmacological characteristics based on its specific molecular structure, enzyme inhibition profile and pharmacokinetic properties. Each PDE5 inhibitor has a distinct selectivity that contributes to its safety profile. As with all new drugs, and especially those in a new class, careful evaluation will be necessary to ensure the optimal use of the PDE5 inhibitors. PMID:12166544

  3. Selective Phosphodiesterase 4B Inhibitors: A Review

    PubMed Central

    Azam, Mohammed Afzal; Tripuraneni, Naga Srinivas

    2014-01-01

    Abstract Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B. PMID:25853062

  4. [The Use of Arginine Vasopressin and PhosphodiesteraseIII Inhibitor for Circulatory Shock after the Resection of a Massive Adrenal Pheochromocytoma].

    PubMed

    Nagamine, Yusuke; Nishinarita, Reiko; Mizutani, Kenji; Goto, Takahisa

    2016-06-01

    A 72-year-old man developed hypertensive crisis five month previously, and was diagnosed with massive adrenal pheochromocytoma, with a diameter of 14.5 cm. Preoperative echocardiography revealed normal cardiac function. The open abdominal surgery was performed under general anesthesia. During manipulation of the tumor he developed hypertension and tachycardia. Severe hypotension (50/25 mmHg) and mild bradycardia (70 beats x min(-1)) followed the resection of the tumor. In addition to volume replacement noradrenaline and adrenaline were administered, but the systolic blood pressure rose only to 60-70 mmHg. In order to treat vasodilatory shock, we started to administer arginine vasopressin infusion at 0.03 units x min(-1). His systolic blood pressure rose to 90 mmHg. The patient was transferred to the intensive care unit (ICU) postoperatively. The echocardiography revealed diffuse hypokinetic cardiac function. In order to treat cardiogenic shock, we started to administer olprinone (phosphodiesteraseIII inhibitor, infusion of 0.1 μg x kg(-1) x min(-1)). On postoperative day 2, circulatory shock improved and the patient was discharged from the ICU. In conclusion, circulatory shock after the resection of a massive pheochromocytoma was due to the down regulation of α and β adrenergic receptors. The non-adrenergic vasoconstrictor and inotrope were useful for this situation. PMID:27483661

  5. Current use of phosphodiesterase inhibitors in urology

    PubMed Central

    Hakky, Tariq Said; Jain, Lakshay

    2015-01-01

    The causes of male erectile dysfunction (ED) are quite variable and are now commonly divided into etiologies such as ischemia, smooth muscle damage, or altered blood flow. Although varying rates of ED have been reported in literature, the number of men with ED is projected to increase worldwide by 2025 to approximately 322 million. Since the introduction of phosphodiesterase 5 (PDE5) inhibitors, there has been a paradigm shift in the treatment of ED because PDE5 inhibitors address a broad spectrum of etiologies for ED. Today, the American Urological Association recommends the use of three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) as a first-line therapy for the treatment of ED. This review evaluates the pharmacological mechanism of PDE5 inhibitors along with the impact and use of sildenafil, vardenafil, tadalafil, and avanafil. By increasing intracellular cGMP levels, PDE5 inhibitors have been shown to be effective in the treatment of ED. Through their effects on other cellular signaling pathways, PDE5 inhibitors have the potential for treating other urologic conditions as well. The use of PDE5 inhibitors can also be combined to produce a synergistic effect in conditions such as male hypogonadism and benign prostatic hyperplasia in addition to ED. PMID:26328208

  6. Predictive QSAR modeling of phosphodiesterase 4 inhibitors.

    PubMed

    Kovalishyn, Vasyl; Tanchuk, Vsevolod; Charochkina, Larisa; Semenuta, Ivan; Prokopenko, Volodymyr

    2012-02-01

    A series of diverse organic compounds, phosphodiesterase type 4 (PDE-4) inhibitors, have been modeled using a QSAR-based approach. 48 QSAR models were compared by following the same procedure with different combinations of descriptors and machine learning methods. QSAR methodologies used random forests and associative neural networks. The predictive ability of the models was tested through leave-one-out cross-validation, giving a Q² = 0.66-0.78 for regression models and total accuracies Ac=0.85-0.91 for classification models. Predictions for the external evaluation sets obtained accuracies in the range of 0.82-0.88 (for active/inactive classifications) and Q² = 0.62-0.76 for regressions. The method showed itself to be a potential tool for estimation of IC₅₀ of new drug-like candidates at early stages of drug development. PMID:22023934

  7. [Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

    PubMed

    Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

    2015-01-01

    In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively. PMID:26047999

  8. Cardiac uses of phosphodiesterase-5 inhibitors.

    PubMed

    Schwartz, Bryan G; Levine, Laurence A; Comstock, Gary; Stecher, Vera J; Kloner, Robert A

    2012-01-01

    Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases. PMID:22192662

  9. Anti-platelet therapy: phosphodiesterase inhibitors

    PubMed Central

    Gresele, Paolo; Momi, Stefania; Falcinelli, Emanuela

    2011-01-01

    Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) are two critical intracellular second messengers provided with strong inhibitory activity on fundamental platelet functions. Phosphodiesterases (PDEs), by catalysing the hydrolysis of cAMP and cGMP, limit the intracellular levels of cyclic nucleotides, thus regulating platelet function. The inhibition of PDEs may therefore exert a strong platelet inhibitory effect. Platelets possess three PDE isoforms (PDE2, PDE3 and PDE5), with different selectivity for cAMP and cGMP. Several nonselective or isoenzyme-selective PDE inhibitors have been developed, and some of them have entered clinical use as antiplatelet agents. This review focuses on the effect of PDE2, PDE3 and PDE5 inhibitors on platelet function and on the evidence for an antithrombotic action of some of them, and in particular of dipyridamole and cilostazol. PMID:21649691

  10. Phosphodiesterase type 5 inhibitors in pulmonary arterial hypertension.

    PubMed

    Montani, David; Chaumais, Marie-Camille; Savale, Laurent; Natali, Delphine; Price, Laura C; Jaïs, Xavier; Humbert, Marc; Simonneau, Gérald; Sitbon, Olivier

    2009-09-01

    Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and

  11. The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1).

    PubMed

    Schafer, Peter H; Chen, Peng; Fang, Lorraine; Wang, Andrew; Chopra, Rajesh

    2015-01-01

    Apremilast, an oral phosphodiesterase 4 inhibitor, demonstrated effectiveness (versus placebo) for treatment of active psoriatic arthritis in the psoriatic arthritis long-term assessment of clinical efficacy (PALACE) phase III clinical trial program. Pharmacodynamic effects of apremilast on plasma biomarkers associated with inflammation were evaluated in a PALACE 1 substudy. Of 504 patients randomized in PALACE 1, 150 (placebo: n = 51; apremilast 20 mg BID: n = 51; apremilast 30 mg BID: n = 48) provided peripheral blood plasma samples for analysis in a multiplexed cytometric bead array assay measuring 47 proteins associated with systemic inflammatory immune responses. Association between biomarker levels and achievement of 20% improvement from baseline in modified American College of Rheumatology (ACR20) response criteria was assessed by logistic regression. At Week 24, IL-8, TNF-α, IL-6, MIP-1β, MCP-1, and ferritin were significantly reduced from baseline with apremilast 20 mg BID or 30 mg BID versus placebo. ACR20 response correlated with change in TNF-α level with both apremilast doses. At Week 40, IL-17, IL-23, IL-6, and ferritin were significantly decreased and IL-10 and IL-1 receptor antagonists significantly increased with apremilast 30 mg BID versus placebo. In patients with active psoriatic arthritis, apremilast reduced circulating levels of Th1 and Th17 proinflammatory mediators and increased anti-inflammatory mediators. PMID:25973439

  12. The Pharmacodynamic Impact of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, on Circulating Levels of Inflammatory Biomarkers in Patients with Psoriatic Arthritis: Substudy Results from a Phase III, Randomized, Placebo-Controlled Trial (PALACE 1)

    PubMed Central

    Schafer, Peter H.; Chen, Peng; Fang, Lorraine; Wang, Andrew; Chopra, Rajesh

    2015-01-01

    Apremilast, an oral phosphodiesterase 4 inhibitor, demonstrated effectiveness (versus placebo) for treatment of active psoriatic arthritis in the psoriatic arthritis long-term assessment of clinical efficacy (PALACE) phase III clinical trial program. Pharmacodynamic effects of apremilast on plasma biomarkers associated with inflammation were evaluated in a PALACE 1 substudy. Of 504 patients randomized in PALACE 1, 150 (placebo: n = 51; apremilast 20 mg BID: n = 51; apremilast 30 mg BID: n = 48) provided peripheral blood plasma samples for analysis in a multiplexed cytometric bead array assay measuring 47 proteins associated with systemic inflammatory immune responses. Association between biomarker levels and achievement of 20% improvement from baseline in modified American College of Rheumatology (ACR20) response criteria was assessed by logistic regression. At Week 24, IL-8, TNF-α, IL-6, MIP-1β, MCP-1, and ferritin were significantly reduced from baseline with apremilast 20 mg BID or 30 mg BID versus placebo. ACR20 response correlated with change in TNF-α level with both apremilast doses. At Week 40, IL-17, IL-23, IL-6, and ferritin were significantly decreased and IL-10 and IL-1 receptor antagonists significantly increased with apremilast 30 mg BID versus placebo. In patients with active psoriatic arthritis, apremilast reduced circulating levels of Th1 and Th17 proinflammatory mediators and increased anti-inflammatory mediators. PMID:25973439

  13. Characterization of inhibitors of phosphodiesterase 1C on a human cellular system.

    PubMed

    Dunkern, Torsten R; Hatzelmann, Armin

    2007-09-01

    Different inhibitors of the Ca(2+)/calmodulin-stimulated phosphodiesterase 1 family have been described and used for the examination of phosphodiesterase 1 in cellular, organ or animal models. However, the inhibitors described differ in potency and selectivity for the different phosphodiesterase family enzymes, and in part exhibit additional pharmacodynamic actions. In this study, we demonstrate that phosphodiesterase 1C is expressed in the human glioblastoma cell line A172 with regard to mRNA, protein and activity level, and that lower activities of phosphodiesterase 2, phosphodiesterase 3, phosphodiesterase 4 and phosphodiesterase 5 are also present. The identity of the phosphodiesterase 1C activity detected was verified by downregulation of the mRNA and protein through human phosphodiesterase 1C specific small interfering RNA. In addition, the measured K(m) values (cAMP, 1.7 microm; cGMP, 1.3 microm) are characteristic of phosphodiesterase 1C. We demonstrate that treatment with the Ca(2+) ionophore ionomycin increases intracellular Ca(2+) in a concentration-dependent way without affecting cell viability. Under conditions of enhanced intracellular Ca(2+) concentration, a rapid increase in cAMP levels caused by the adenylyl cyclase activator forskolin was abolished, indicating the involvement of Ca(2+)-activated phosphodiesterase 1C. The reduction of forskolin-stimulated cAMP levels was reversed by phosphodiesterase 1 inhibitors in a concentration-dependent way. Using this cellular system, we compared the cellular potency of published phosphodiesterase 1 inhibitors, including 8-methoxymethyl-3-isobutyl-1-methylxanthine, vinpocetine, SCH51866, and two established phosphodiesterase 1 inhibitors developed by Schering-Plough (named compounds 31 and 30). We demonstrate that up to 10 microm 8-methoxymethyl-3-isobutyl-1-methylxanthine and vinpocetine had no effect on the reduction of forskolin-stimulated cAMP levels by ionomycin, whereas the more selective and up to 10

  14. Phosphodiesterase inhibitors for the treatment of pulmonary hypertension.

    PubMed

    Wilkins, M R; Wharton, J; Grimminger, F; Ghofrani, H A

    2008-07-01

    The pulmonary vascular bed is both a source of and target for a number of vasoactive factors. Among the most important for pulmonary vascular homeostasis are factors that utilise cyclic guanosine monophosphate (cGMP) as an intracellular second messenger. These include nitric oxide and the natriuretic peptide family (atrial, brain and C-type natriuretic peptides). In the search for therapeutic strategies that engage the cGMP signalling pathway for the treatment of pulmonary arterial hypertension (PAH), inhibition of cGMP metabolism by phosphodiesterase type 5 (PDE5)-targeted compounds has proven most successful to date. One PDE5 inhibitor, sildenafil, has been shown to improve pulmonary haemodynamics and exercise capacity in patients with PAH and is now an approved treatment. Others are under investigation. An interesting, although still tentative, observation is the potential of sildenafil to reduce pulmonary vascular resistance without adversely affecting ventilation-perfusion matching. Another is the expression of phosphodiesterase type 5 in the hypertrophied right ventricle. These data suggest that phosphodiesterase type 5 inhibitors may have effects that distinguish them from other treatments for pulmonary hypertension and merit further study. PMID:18591337

  15. Thromboangiitis obliterans successfully treated with phosphodiesterase type 5 inhibitors.

    PubMed

    Abeles, Aryeh M; Nicolescu, Mirela; Pinchover, Zachary; Abeles, Micha

    2014-08-01

    Thromboangiitis obliterans, or Buerger's disease, is a non-atherosclerotic, segmental, inflammatory disease affecting the small- and medium-sized vessels of the distal extremities. Other than discontinuation of tobacco, there is no standard-of-care treatment. Although two randomized trials have demonstrated a role for intravenous iloprost, no oral drug has yet been demonstrated to be effective in treating thromboangiitis obliterans. We present the first three reported cases of thromboangiitis obliterans successfully treated with phosphodiesterase type 5 inhibitors, followed by a discussion of the rationale for the use of these agents in thromboangiitis obliterans. PMID:24000082

  16. Therapeutic Utility of Phosphodiesterase Type I Inhibitors in Neurological Conditions

    PubMed Central

    Medina, Alexandre E.

    2011-01-01

    Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions. Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. These neuronal plasticity enhancement properties make PDE1 inhibitors good candidates as therapeutic agents in many neurological conditions. However, the lack of specificity of the drugs currently available poses a challenge to the systematic evaluation of the beneficial effect of these agents. The development of more specific drugs may pave the way for the use of PDE1 inhibitors as therapeutic agents in cases of neurodevelopmental conditions such as fetal alcohol spectrum disorders and in degenerative disorders such as Alzheimer's and Parkinson's. PMID:21373359

  17. Tadalafil: a phosphodiesterase-5 inhibitor for benign prostatic hyperplasia.

    PubMed

    Cantrell, Matthew A; Baye, Jordan; Vouri, Scott Martin

    2013-06-01

    Tadalafil is a phosphodiesterase (PDE)-5 inhibitor recently approved by the United States Food and Drug Administration for lower urinary tracts symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). The mechanism for improved LUTS is thought to be related to three principal theories: alterations in nitric oxide levels, Rho-associated protein kinase deactivation, and reductions in pelvic atherosclerosis. The efficacy of PDE-5 inhibitors for the treatment of LUTS associated with BPH has been demonstrated in several randomized placebo-controlled trials. Tadalafil is thought to be superior based on an extended half-life; however, other PDE-5 inhibitors have positive results in BPH and have not been proved to be inferior to tadalafil. Before administration, concomitant use of medications such as nonselective α-adrenergic antagonists, nitrates, and cytochrome P450 inhibitors should be assessed for possible drug interactions. Potential adverse drug events seen in Food and Drug Administration-approved tadalafil include back pain, dyspepsia, headache, and dizziness. Given the efficacy and safety data currently available, the PDE-5 inhibitor tadalafil represents a reasonable alternative for selected male patients with LUTS associated with BPH, especially with concomitant erectile dysfunction. PMID:23529917

  18. Phosphodiesterase 4D Inhibitors Limit Prostate Cancer Growth Potential

    PubMed Central

    Powers, Ginny L.; Hammer, Kimberly D.P.; Domenech, Maribella; Frantskevich, Katsiaryna; Malinowski, Rita L.; Bushman, Wade; Beebe, David J.; Marker, Paul C.

    2014-01-01

    Phosphodiesterase 4D (PDE4D) has recently been implicated as a proliferation-promoting factor in prostate cancer and is over-expressed in human prostate carcinoma. However, the effects of PDE4D inhibition using pharmacological inhibitors have not been examined in prostate cancer. These studies examined the effects of selective PDE4D inhibitors, NVP-ABE171 and cilomilast, as anti-prostate cancer therapies in both in vitro and in vivo models. The effects of PDE4D inhibitors on pathways that are critical in prostate cancer and/or downstream of cyclic AMP (cAMP) were examined. Both NVP-ABE171 and cilomilast decreased cell growth. In vitro, PDE4D inhibitors lead to decreased signaling of the sonic hedgehog (SHH), Androgen Receptor (AR), and MAPK pathways, but growth inhibition was best correlated to the sonic hedgehog pathway. PDE4D inhibition also reduced proliferation of epithelial cells induced by paracrine signaling from co-cultured stromal cells that had activated hedgehog signaling. In addition, PDE4D inhibitors decreased the weight of the prostate in wild-type mice. Prostate cancer xenografts grown in nude mice that were treated with cilomilast or NVP-ABE171 had decreased wet weight and increased apoptosis compared to vehicle treated controls. These studies suggest the pharmacological inhibition of PDE4D using small molecule inhibitors is an effective option for prostate cancer therapy. Implications PDE4D inhibitors decrease the growth of prostate cancer cells in vivo and in vitro, and PDE4D inhibition has therapeutic potential in prostate cancer. PMID:25149359

  19. Attenuation by phosphodiesterase inhibitors of lipopolysaccharide-induced thromboxane release and bronchoconstriction in rat lungs.

    PubMed

    Uhlig, S; Featherstone, R L; Held, H D; Nüsing, R; Schudt, C; Wendel, A

    1997-12-01

    Exposure of perfused rat lungs to lipopolysaccharides (LPS) causes induction of cyclooxygenase-2 followed by thromboxane (TX)-mediated bronchoconstriction (BC). Recently, phosphodiesterase (PDE) inhibitors have received much interest because they not only are bronchodilators but also can suppress release of proinflammatory mediators. In the present study, we investigated the effect of three different PDE inhibitors on TX release and BC in LPS-exposed perfused rat lungs. The PDE inhibitors used were motapizone (PDE III specific), rolipram (PDE IV specific), and zardaverine (mixed PDE III and IV specific). At 5 microM, a concentration at which all three compounds selectively block their respective PDE isoenzyme, rolipram (IC50 = 0.04 microM) and zardaverine (IC50 = 1.8 microM) largely attenuated the LPS-induced BC, whereas motapizone was almost ineffective (IC50 = 40 microM). In contrast to LPS, BC induced by the TX-mimetic U46619 was prevented with comparable strength by motapizone and rolipram. In LPS-treated lungs, the TX release was reduced to 50% of controls by rolipram and zardaverine but was unaltered in the presence of 5 microM motapizone. Increasing intracellular cAMP through perfusion of db-cAMP or forskolin (activates adenylate cyclase) also reduced TX release and BC. We conclude that PDE inhibitors act via elevation of intracellular cAMP. Although both PDE III and PDE IV inhibitors can relax airway smooth muscle, in the model of LPS-induced BC, PDE IV inhibitors are more effective because (in contrast to PDE III inhibitors) they also attenuate TX release. PMID:9400021

  20. AB030. Evolution of phosphodiesterase type 5 inhibitors

    PubMed Central

    Moon, Du Geon

    2016-01-01

    After launching of sildenafil citrate, the last invention of 20th century, in 1998, oral phosphodiesterase type 5 (PDE5) inhibitor has been established as first line treatment of erectile dysfunction and shift new paradigm of diagnosis and treatment of erectile dysfunction. The big success of sildenafil in pharmaceutical R&D induced the consecutive development of the so-called ‘The second Viagra’, e.g., tadalafil and vardenafil in 2003. Currently, these 3 kinds of PDE5 inhibitors are most famous and well-known PDE5 inhibitors worldwide. From the early competition, PDE5 inhibitors have been continuously evolved through completion for survival. In Korea, another 3 kinds of PDE5 inhibitors, udenafil [2005], mirodenafil [2007] and avanafil [2011] have been developed. Additionally 60 generic sildenafils from 49 companies were released with termination of sildenafil patent in Korea, 2012 and 160 generic tadalafils from 64 companies were released with termination of tadalafil patent in Korea, 2015. Besides of Korea PDE5I, generic sildenafil and generic tadalafil induce cheaper PDE5I, as much as 1/5 of original PDE5Is. The dosage concept also evolved from on-demand to daily low-dose and alternative dosage. These changes of dosage concept was proved from safety of daily use and indication of PDE5Is for ED also evolved beyond ED and widened to pulmonary hypertension of Sildenafil, benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) of tadalafil and penile rehabilitation after RRP. For the launching of Generic PDE5Is, the preparation also evolved from tablet to orodisposable film, granule and chewable. The orodisposable film and chewable is favorable from patients. In Korea, the impact of recent generic tadalafil is totally different from those of generic Sildenafil in 2012. The long half-life of tadalafil enabled the approval for BPH/LUTS with daily low dose usage. In turn, the generic Cialis also will be developed as various preparations including

  1. The Wonders of Phosphodiesterase-5 Inhibitors: A Majestic History

    PubMed Central

    Elhwuegi, AS

    2016-01-01

    The Nobel Prize winning discovery of nitric oxide (NO) in 1986 was the starting point for a new innovation in drug discovery. NO acting as a mediator at different physiological systems is believed to be involved in many physiological and pathological conditions through the formation of the second messenger cyclic guanosine monophosphate (cGMP). cGMP-dependent vasodilation effect of NO is important in regulating pulmonary and systemic pressures, maintaining penis erection, preventing atherosclerosis, preventing platelet aggregation, and protecting and controlling cardiac functions. The main enzyme involved in the termination of cGMP effects is phosphodiesterase enzyme 5 (PDE-5), which is overexpressed in ventricular hypertrophy and heart failure. A milestone in drug discovery was the selective inhibitors of PDE-5 that developed to be a multibillion dollar blockbuster in drug market. PDE-5 inhibitors are approved for the treatment of erectile dysfunctions (EDs), pulmonary hypertension, and benign prostatic hypertrophy. They are also under clinical trials for their cardiac protection against damage induced by ischemia or heart failure. This review article is an update about the pharmacotherapeutics of PDE-5 inhibitors and the majestic history that led to their discovery. The information reported in this review was obtained from the electronic sources of different databases such as PubMed Central, Google Scholar, and Scopus. Keywords used for search included cGMP (mechanisms and functions), EDs (drugs used), nitric oxide, and PDE-5 inhibitors (clinical applications). A total of 165 articles were studied, of which 45 articles were referred to in this review. PMID:27398244

  2. The Wonders of Phosphodiesterase-5 Inhibitors: A Majestic History.

    PubMed

    Elhwuegi, A S

    2016-01-01

    The Nobel Prize winning discovery of nitric oxide (NO) in 1986 was the starting point for a new innovation in drug discovery. NO acting as a mediator at different physiological systems is believed to be involved in many physiological and pathological conditions through the formation of the second messenger cyclic guanosine monophosphate (cGMP). cGMP-dependent vasodilation effect of NO is important in regulating pulmonary and systemic pressures, maintaining penis erection, preventing atherosclerosis, preventing platelet aggregation, and protecting and controlling cardiac functions. The main enzyme involved in the termination of cGMP effects is phosphodiesterase enzyme 5 (PDE-5), which is overexpressed in ventricular hypertrophy and heart failure. A milestone in drug discovery was the selective inhibitors of PDE-5 that developed to be a multibillion dollar blockbuster in drug market. PDE-5 inhibitors are approved for the treatment of erectile dysfunctions (EDs), pulmonary hypertension, and benign prostatic hypertrophy. They are also under clinical trials for their cardiac protection against damage induced by ischemia or heart failure. This review article is an update about the pharmacotherapeutics of PDE-5 inhibitors and the majestic history that led to their discovery. The information reported in this review was obtained from the electronic sources of different databases such as PubMed Central, Google Scholar, and Scopus. Keywords used for search included cGMP (mechanisms and functions), EDs (drugs used), nitric oxide, and PDE-5 inhibitors (clinical applications). A total of 165 articles were studied, of which 45 articles were referred to in this review. PMID:27398244

  3. Ciprofloxacin-Induced Antibacterial Activity Is Attenuated by Phosphodiesterase Inhibitors

    PubMed Central

    Masadeh, Majed M.; Alzoubi, Karem H.; Khabour, Omar F.; Al-Azzam, Sayer I.

    2014-01-01

    Background Ciprofloxacin is a commonly used antibiotic for urinary tract infection that interacts with bacterial topoisomerases leading to oxidative radicals generation and bacterial cell death. Phosphodiesterase inhibitors (PDEis), on the other hand, are commonly used drugs for the management of erectile dysfunction. The group includes agents such as sildenafil, vardenafil, and tadalafil. Objectives We investigated whether PDEi could interfere with the antibacterial activity of ciprofloxacin. Methods PDEis were tested in several reference bacteria, including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Acinetobacter baumannii, Proteus mirabilis, and Klebsiella pneumoniae utilizing a standard disc diffusion method and measuring both zones of inhibition and MIC. Results Results from both assays indicated that ciprofloxacin demonstrates potent activity against the tested reference bacteria. Additionally, when bacteria were treated with a combination of ciprofloxacin and sildenafil, tadalafil, or vardenafil, the zones of the combination inhibition were significantly reduced, whereas the MIC values were significantly greater than those of ciprofloxacin alone for all tested bacterial strains. In an attempt to examine the mechanism by which PDEis interfere with the action of ciprofloxacin, we utilized the in vitro E coli DNA gyrase cleavage assay. The results showed that PDEi drugs had no effect on ciprofloxacin’s inhibition of E coli gyrase activity. Conclusions Pretreatment of various reference bacterial cells with PDEis largely inhibited the antibacterial activity of ciprofloxacin. PMID:26649077

  4. The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function.

    PubMed Central

    Murray, K. J.; England, P. J.; Hallam, T. J.; Maguire, J.; Moores, K.; Reeves, M. L.; Simpson, A. W.; Rink, T. J.

    1990-01-01

    1. The effects of siguazodan (SK&F 94836) a selective phosphodiesterase (PDE) inhibitor with inotropic and vasodilator activity, were studied on human platelets. 2. Siguazodan selectively inhibited the major cyclic AMP-hydrolysing PDE in human platelet supernatants. The inhibited enzyme has been variously termed cyclic GMP-inhibited PDE or PDE-III. 3. In platelet-rich plasma (PRP), siguazodan inhibited U46619-induced aggregation more potently than that induced by ADP and collagen. Treatment of the PRP with aspirin had no effect on the potency of siguazodan. 4. In washed platelets, siguazodan increased cyclic AMP levels and reduced cytoplasmic free calcium [( Ca2+]i). ADP decreased the ability of siguazodan to raise cyclic AMP and this may explain its lower potency in inhibiting responses to ADP. 5. Siguazodan has anti-platelet actions over the same concentration range that it is an inotrope and vasodilator. PMID:2158847

  5. Counterfeit phosphodiesterase type 5 inhibitors pose significant safety risks

    PubMed Central

    Jackson, G; Arver, S; Banks, I; Stecher, V J

    2010-01-01

    Counterfeit drugs are inherently dangerous and a growing problem; counterfeiters are becoming increasingly sophisticated. Growth of the counterfeit medication market is attributable in part to phosphodiesterase type 5 inhibitor (PDE5i) medications for erectile dysfunction (ED). Millions of counterfeit PDE5is are seized yearly and account for the bulk of all counterfeit pharmaceutical product seizures. It has been estimated that up to 2.5 million men in Europe are exposed to illicit sildenafil, suggesting that there may be as many illegal as legal users of sildenafil. Analysis of the contents of counterfeit PDE5is shows inconsistent doses of active pharmaceutical ingredients (from 0% to > 200% of labelled dose), contaminants (including talcum powder, commercial paint and printer ink) and alternative ingredients that are potentially hazardous. In one analysis, only 10.1% of samples were within 10% of the labelled tablet strength. Estimates place the proportion of counterfeit medications sold over the Internet from 44% to 90%. Of men who purchase prescription-only medication for ED without a prescription, 67% do so using the Internet. Counterfeit PDE5is pose direct and indirect risks to health, including circumvention of the healthcare system. More than 30% of men reported no healthcare interaction when purchasing ED medications. Because > 65% actually had ED, these men missed an opportunity for evaluation of comorbidities (e.g. diabetes and hypertension). Globally, increased obstacles for counterfeiters are necessary to combat pharmaceutical counterfeiting, including fines and penalties. The worldwide nature of the counterfeit problem requires proper coordination between countries to ensure adequate enforcement. Locally, physicians who treat ED need to inform patients of the dangers of ordering PDE5is via the Internet. PMID:20088883

  6. Counterfeit phosphodiesterase type 5 inhibitors pose significant safety risks.

    PubMed

    Jackson, G; Arver, S; Banks, I; Stecher, V J

    2010-03-01

    Counterfeit drugs are inherently dangerous and a growing problem; counterfeiters are becoming increasingly sophisticated. Growth of the counterfeit medication market is attributable in part to phosphodiesterase type 5 inhibitor (PDE5i) medications for erectile dysfunction (ED). Millions of counterfeit PDE5is are seized yearly and account for the bulk of all counterfeit pharmaceutical product seizures. It has been estimated that up to 2.5 million men in Europe are exposed to illicit sildenafil, suggesting that there may be as many illegal as legal users of sildenafil. Analysis of the contents of counterfeit PDE5is shows inconsistent doses of active pharmaceutical ingredients (from 0% to > 200% of labelled dose), contaminants (including talcum powder, commercial paint and printer ink) and alternative ingredients that are potentially hazardous. In one analysis, only 10.1% of samples were within 10% of the labelled tablet strength. Estimates place the proportion of counterfeit medications sold over the Internet from 44% to 90%. Of men who purchase prescription-only medication for ED without a prescription, 67% do so using the Internet. Counterfeit PDE5is pose direct and indirect risks to health, including circumvention of the healthcare system. More than 30% of men reported no healthcare interaction when purchasing ED medications. Because > 65% actually had ED, these men missed an opportunity for evaluation of comorbidities (e.g. diabetes and hypertension). Globally, increased obstacles for counterfeiters are necessary to combat pharmaceutical counterfeiting, including fines and penalties. The worldwide nature of the counterfeit problem requires proper coordination between countries to ensure adequate enforcement. Locally, physicians who treat ED need to inform patients of the dangers of ordering PDE5is via the Internet. PMID:20088883

  7. Intravenously administered phosphodiesterase 4 inhibitors dilate retinal blood vessels in rats.

    PubMed

    Miwa, Tomoyo; Mori, Asami; Nakahara, Tsutomu; Ishii, Kunio

    2009-01-01

    In the present study, we examined effects of intravenously administered inhibitors of phosphodiesterase 4 (rolipram and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20-1724)) and non-selective inhibitor of phosphodiesterases (theophylline) on diameter of retinal blood vessel and fundus (retinal/choroidal) blood flow in rats. Male Wistar rats (8- to 10-week-old) were treated with tetrodotoxin (50 microg/kg, i.v.) to eliminate any nerve activity and prevent the eye movement under artificial ventilation. Methoxamine was used to maintain adequate systemic circulation. Ocular fundus images were captured with an original high-resolution digital fundus camera for small animals. Diameters of retinal blood vessels contained in the digital images were measured using image-processing softwares on a personal computer. Fundus blood flow was measured using a laser Doppler flow meter. Both rolipram (0.01-10 microg/kg/min, i.v.) and Ro-20-1724 (0.01-10 microg/kg/min, i.v.) increased diameters of retinal blood vessels in a dose-dependent manner without significant effect on systemic blood pressure, heart rate and fundus blood flow. The effects of phosphodiesterase 4 inhibitors on retinal arterioles were greater than those on retinal venules. Similarly, theophylline (0.1-10 mg/kg/min, i.v.) dilated retinal blood vessels, whereas it decreased blood pressure and increased heart rate markedly. These results suggest that phosphodiesterase 4 contributes to maintenance of retinal vascular tone. Inhibitors of phosphodiesterase 4 could be considered as a candidate for therapeutic drugs to treat diseases associated with disorders of retinal circulation without severe cardiovascular side-effects. PMID:19027003

  8. Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure

    PubMed Central

    Jaiswal, Abhishek; Nguyen, Vinh Q; Le Jemtel, Thierry H; Ferdinand, Keith C

    2016-01-01

    In advanced heart failure (HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase III inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guideline-directed HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker (BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF. PMID:27468333

  9. Effects of Intrarenal and Intravenous Infusion of the Phosphodiesterase 3 Inhibitor Milrinone on Renin Secretion

    NASA Technical Reports Server (NTRS)

    Kumagai, Kazuhiro; Reid, Ian A.

    1994-01-01

    We have reported that administration of the phosphodiesterase III inhibitor milrinone increases renin secretion in conscious rabbits. The aim of the present study was to determine if the increase in renin secretion results from a direct renal action of milrinone, or from an indirect extrarenal effect of the drug. This was accomplished by comparing the effects of intrarenal and intravenous infusion of graded doses of milrinone on plasma renin activity in unilaterally nephrectomized conscious rabbits. Milrinone was infused into the renal artery in doses of 0.01, 0.1 and 1.0 micro-g/kg/min, and intravenously in the same rabbits in doses of 0.01, 0.1, 1.0 and 10 micro-g/kg/min. Each dose was infused for 15 min. No intrarenal dose of milrinone altered plasma renin activity or arterial pressure, although at the highest dose, there was a small increase in heart rate. Intravenous infusion of milrinone at 1.0 micro-g/kg/min increased plasma renin activity to 176 +/- 55% of the control value (P less than 0.05). Heart rate increased but arterial pressure did not change. Intravenous infusion of milrinone at 1O micro-g/kg/min increased plasma renin activity to 386 +/- 193% of control in association with a decrease in arterial pressure and an increase in heart rate. These results confirm that milrinone increases renin secretion, and indicate that the stimulation is due to an extrarenal effect of the drug.

  10. Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure.

    PubMed

    Jaiswal, Abhishek; Nguyen, Vinh Q; Le Jemtel, Thierry H; Ferdinand, Keith C

    2016-07-26

    In advanced heart failure (HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase III inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guideline-directed HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker (BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF. PMID:27468333

  11. Phosphodiesterase 10A inhibitors: analysis of US/EP patents granted since 2012.

    PubMed

    Bartolomé-Nebreda, José-Manuel; Conde-Ceide, Susana; García, María

    2015-01-01

    Phosphodiesterases are enzymes that metabolically inactivate the intracellular second messengers 3',5'-cyclic adenosine and guanosine monophosphate contributing to the control of multiple biological processes. Among them, PDE10A has the most restricted distribution with high expression in striatal medium spiny neurons. Dysfunction of this key brain circuit has been associated with different psychiatric and neurodegenerative disorders. The unique role of PDE10A, together with its increased pharmacological characterization, have prompted enormous interest in investigating the potential of inhibitors of this enzyme as potential novel therapeutic agents This article reviews PDE10A related patents issued in the period 2012-2014 in the USA and Europe offering also a perspective on potential avenues for the future clinical development of phosphodiesterase 10A inhibitors. PMID:26030079

  12. The role of phosphodiesterase inhibitors in the management of pulmonary vascular diseases

    PubMed Central

    Butrous, Ghazwan

    2014-01-01

    Phosphodiesterase inhibitors (PDE) can be used as therapeutic agents for various diseases such as dementia, depression, schizophrenia and erectile dysfunction in men, as well as congestive heart failure, chronic obstructive pulmonary disease, rheumatoid arthritis, other inflammatory diseases, diabetes and various other conditions. In this review we will concentrate on one type of PDE, mainly PDE5 and its role in pulmonary vascular diseases. PMID:25780785

  13. Chronic Low Dosing of Phosphodiesterase Type 5 Inhibitor for Erectile Dysfunction

    PubMed Central

    Sung, Hyun Hwan

    2012-01-01

    Oral phosphodiesterase type 5 (PDE5) inhibitors have provided non-invasive, effective, and well-tolerated treatments for patients with erectile dysfunction (ED). However, many patients with ED are unresponsive to 'on-demand' PDE5 inhibitors. In addition, the lack of spontaneity and naturalness of the on-demand regimen could be a reason for decreased compliance with PDE5 inhibitors. Recently, tadalafil and udenafil were approved for low-dose daily administration for the treatment of ED. Since the introduction of the concept of daily administration of PDE5 inhibitors, several reports have supported the potential benefits of this therapy for disease modification, improvement of the treatment response in difficult-to-treat populations, spontaneity, and safety, although further research is needed to better address these hypotheses. In this article, we reviewed the daily administration of PDE5 inhibitors in terms of pharmacokinetics, safety, efficacy, and distinct features. PMID:22741044

  14. Phosphodiesterase type 5 inhibitors as a treatment for erectile dysfunction: Current information and new horizons

    PubMed Central

    Ferguson, James E.; Carson, Culley C.

    2013-01-01

    Introduction Over the past 15 years, the discovery and development of oral medications that selectively inhibit the enzyme phosphodiesterase type 5 (PDE5) have revolutionised the treatment of erectile dysfunction (ED). Currently, three PDE5 inhibitors are widely available clinically, i.e., sildenafil, vardenafil and tadalafil. New PDE5 inhibitors, including avanafil and udenafil, are now in clinical use in a few countries, and other compounds are under development. Methods We describe the current use and future direction of PDE5 inhibitors in the treatment of ED. Results and conclusion Each PDE5 inhibitor has an excellent and comparable efficacy and tolerability. These drugs are highly effective for ED of various causes, and are effective in preventing ED after radical prostatectomy. However, whilst being at least 60% effective, PDE5 inhibitors are still ineffective in at least 30% of patients, prompting current research into other pharmacological targets for ED. PMID:26558086

  15. Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics.

    PubMed

    Tenor, Hermann; Hatzelmann, Armin; Beume, Rolf; Lahu, Gezim; Zech, Karl; Bethke, Thomas D

    2011-01-01

    Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties. PMID:21695636

  16. Phosphodiesterase-5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation, Neurodegeneration, and Cognition

    PubMed Central

    Peixoto, Christina Alves; Nunes, Ana Karolina Santana; Garcia-Osta, Ana

    2015-01-01

    Phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a potential therapeutic strategy for neuroinflammatory, neurodegenerative, and memory loss diseases. Mechanistically, PDE5-Is produce an anti-inflammatory and neuroprotection effect by increasing expression of nitric oxide synthases and accumulation of cGMP and activating protein kinase G (PKG), the signaling pathway of which is thought to play an important role in the development of several neurodiseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The aim of this paper was to review present knowledge of the signaling pathways that underlie the use of PDE5-Is in neuroinflammation, neurogenesis, learning, and memory. PMID:26770022

  17. An Insight into the Pharmacophores of Phosphodiesterase-5 Inhibitors from Synthetic and Crystal Structural Studies

    SciTech Connect

    Chen,G.; Wang, H.; Robinson, H.; Cai, J.; Wan, Y.; Ke, H.

    2008-01-01

    Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDE5 catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1, 6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660-683), which is different from any of the known PDE5 structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5 Angstroms . The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required.

  18. Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2

    PubMed Central

    Hornyak, Peter; Askwith, Trevor; Walker, Sarah; Komulainen, Emilia; Paradowski, Michael; Pennicott, Lewis E.; Bartlett, Edward J.; Brissett, Nigel C.; Raoof, Ali; Watson, Mandy; Jordan, Allan M.; Ogilvie, Donald J.; Ward, Simon E.; Atack, John R.; Pearl, Laurence H.; Caldecott, Keith W.; Oliver, Antony W.

    2016-01-01

    Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5′-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for high-throughput screen (HTS)-screening. We have gone on to determine crystal structures of these compounds bound to a ‘humanized’ form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2. PMID:27099339

  19. Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2.

    PubMed

    Hornyak, Peter; Askwith, Trevor; Walker, Sarah; Komulainen, Emilia; Paradowski, Michael; Pennicott, Lewis E; Bartlett, Edward J; Brissett, Nigel C; Raoof, Ali; Watson, Mandy; Jordan, Allan M; Ogilvie, Donald J; Ward, Simon E; Atack, John R; Pearl, Laurence H; Caldecott, Keith W; Oliver, Antony W

    2016-07-01

    Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5'-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for high-throughput screen (HTS)-screening. We have gone on to determine crystal structures of these compounds bound to a 'humanized' form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2. PMID:27099339

  20. Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors.

    PubMed

    Dresser, M J; Desai, D; Gidwani, S; Seftel, A D; Modi, N B

    2006-01-01

    Potential pharmacokinetic interactions between dapoxetine, a serotonin transporter inhibitor developed for the treatment of premature ejaculation (PE), and the phosphodiesterase-5 inhibitors tadalafil and sildenafil, agents used in the treatment of erectile dysfunction (ED), were investigated in an open-label, randomized, crossover study (n=24 men) comparing dapoxetine 60 mg, dapoxetine 60 mg+tadalafil 20 mg, and dapoxetine 60 mg+sildenafil 100 mg. Plasma concentrations of dapoxetine, tadalafil, and sildenafil were determined by liquid chromatography-tandem mass spectrometry. Tadalafil did not affect the pharmacokinetics of dapoxetine, whereas sildenafil increased the dapoxetine AUCinf by 22%; these effects were deemed not clinically important. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil. Most adverse events were mild in nature. Thus, dapoxetine has no clinically important pharmacokinetic interactions with tadalafil or sildenafil, and the combinations are well tolerated. PMID:16307008

  1. Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice.

    PubMed

    Kinoshita, T; Kobayashi, S; Ebara, S; Yoshimura, Y; Horiuchi, H; Tsutsumimoto, T; Wakabayashi, S; Takaoka, K

    2000-12-01

    The administration of either Pentoxifylline (PTX), a methylxanthine derivative and an inhibitor of cyclic AMP (c-AMP) phosphodiesterases (PDEs), or Rolipram, an inhibitor specific to type-4 PDE (PDE4) in normal mice, significantly increased both cortical and cancellous bone mass. Vertebrae and tibiae from mice treated with PTX or Rolipram were analyzed by means of bone densitometry and histomorphometry. The results revealed that both PTX and Rolipram increased bone mass in normal mice mainly through the acceleration of bone formation. These findings suggest that both PTX and Rolipram can enhance physiological bone formation and thereby increase bone mass in normal mice. The possibility that these agents may be of value for the treatment of osteoporosis is discussed. PMID:11113392

  2. Structures of the Four Subfamilies of Phosphodiesterase-4 Provide Insight into the Selectivity of Their Inhibitors

    SciTech Connect

    Wang, H.; Peng, M; Chen , Y; Geng, J; Robinson, H; Houslay , M; Cai, J; Ke, H

    2007-01-01

    PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as potential therapeutics for the treatment of both depression and major inflammatory diseases, but their practical application has been compromised by side effects. A possible cause for the side effects is that current PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4 subfamilies. The development of PDE4 subfamily-selective inhibitors has been hampered by a lack of structural information. In the present study, we rectify this by providing the crystal structures of the catalytic domains of PDE4A, PDE4B and PDE4D in complex with the PDE4 inhibitor NVP 4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid as well as the unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. However, detailed structural comparison reveals significant conformational differences. Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows significant displacements of the residues next to the invariant glutamine residue that is critical for substrate and inhibitor binding. PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors.

  3. Phosphodiesterase-5 inhibitors in management of pulmonary hypertension: safety, tolerability, and efficacy

    PubMed Central

    Buckley, Mitchell S; Staib, Robin L; Wicks, Laura M; Feldman, Jeremy P

    2010-01-01

    Pulmonary arterial hypertension (PAH) is a progressive disease that causes severe disability and has no cure. Over the past 20 years, a variety of treatment options have evolved for the management of PAH. With an expanded therapeutic armamentarium come more complex decisions regarding treatment options. Agent selection depends upon several factors including efficacy, side effect profile, and cost, as well as convenience of administration. We have undertaken a review of phosphodiesterase-5 (PDE-5) inhibitors in PAH with a focus on efficacy and safety. A literature search was conducted using the Medline and Cochrane Central Register of Controlled Trials databases (1966–February 2010) for relevant randomized clinical studies. Overall, 10 studies met our inclusion criteria. Sildenafil was the most commonly studied agent, followed by tadalafil and vardenafil. Most trials found that the PDE-5 inhibitors significantly improved exercise capacity and lowered pulmonary pressures. However, there were conflicting results regarding these agents’ impact on improving cardiac function and functional class. Overall, these medications were effective and well tolerated with a relatively benign side effect profile. The PDE-5 inhibitors are an important option in treating PAH. While most of the published clinical data involved sildenafil, the other PDE-5 inhibitors show promise as well. Further studies are needed to determine the optimal doses of this therapeutic drug class, as well as its effects as adjunctive therapy with other agents in PAH. PMID:21701627

  4. Effectiveness and safety of phosphodiesterase 5 inhibitors in patients with cardiovascular disease and hypertension.

    PubMed

    Chrysant, Steven G

    2013-10-01

    Phosphodiesterase 5 (PDE 5) inhibitors are selective inhibitors of the enzyme PDE 5, which catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP), a potent vasodilator and nitric oxide (NO) donor, to its corresponding metabolites (monophosphates). The enzyme PDE 5 is widely distributed in the body, including the heart and blood vessels. Because of its distribution, it was hypothesized that its inhibition could lead to significant coronary vasodilation, which would benefit patients with coronary artery disease (CAD). This hypothesis led to the development of PDE 5 inhibitors with the first being sildenafil citrate. Subsequent studies with sildenafil in patients with CAD demonstrated a modest cardiovascular effect, but a potent action on penile erection in men, resulting in sildenafil becoming a first-line therapy of erectile dysfunction (ED). Subsequently, two more PDE 5 inhibitors (vardenafil and tadalafil) were developed and approved by the Food and Drug Administration (FDA) for the treatment of ED. Recent studies have shown several pleiotropic beneficial effects of PDE 5 inhibitors in patients with CAD, hypertension, heart failure, pulmonary arterial hypertension, diabetes mellitus and Raynaud's phenomenon. Side effects and interactions of PDE 5 inhibitors with other drugs have been minimal, with the exception of their coadministration with nitrates, which could lead to severe vasodilation and hypotension and therefore, their coadministration is prohibited. All these pleiotropic cardiovascular effects of PDE 5 inhibitors and their drug interactions will be discussed in this concise review in the context of the American College of Cardiology / American Heart Association guidelines and the recent developments in this field. PMID:23917809

  5. Usage and perceptions of phosphodiesterase type 5 inhibitors among the male partners of infertile couples

    PubMed Central

    Kim, Dong Suk; Shim, Sung Han; Lim, Jung Jin; Yang, Seung Choul

    2016-01-01

    Objective We aimed to investigate the prevalence of erectile dysfunction (ED) and the usage of phosphodiesterase type 5 (PDE5) inhibitors for ED treatment in infertile couples. Methods A total of 260 male partners in couples reporting infertility lasting at least 1 year were included in this study. In addition to an evaluation of infertility, all participants completed the International Index of Erectile Function (IIEF)-5 questionnaire to evaluate their sexual function. The participants were asked about their use of PDE5 inhibitors while trying to conceive during their partner's ovulatory period and about their concerns regarding the risks of PDE5 inhibitor use to any eventual pregnancy and/or the fetus. Results Based on the IIEF-5 questionnaire, 41.5% of the participants (108/260) were classified as having mild ED (an IIEF-5 score of 17–21), while 10.4% of the participants (27/260) had greater than mild ED (an IIEF-5 score of 16 or less). The majority (74.2%, 193/260) of male partners of infertile couples had a negative perception of the safety of using a PDE5 inhibitor while trying to conceive. Only 11.1% of men (15/135) with ED in infertile couples had used a PDE5 inhibitor when attempting conception. Conclusion ED was found to be common in the male partners of infertile couples, but the use of PDE5 inhibitors among these men was found to be very low. The majority of male partners were concerned about the risks of using PDE5 inhibitors when attempting to conceive. Appropriate counseling about this topic and treatment when necessary would likely be beneficial to infertile couples in which the male partner has ED. PMID:27104154

  6. Toward a new ‘EPOCH’: optimising treatment outcomes with phosphodiesterase type 5 inhibitors for erectile dysfunction

    PubMed Central

    Sadovsky, R; Brock, G B; Gutkin, S W; Sorsaburu, S

    2009-01-01

    Despite the marked adverse impacts of erectile dysfunction (ED) on quality of life and well-being, many patients (and/or their partners) do not seek medical attention for this problem, do not receive treatment or discontinue such treatment even when it has effectively restored erectile responses to sexual stimulation. Phosphodiesterase type 5 (PDE5) inhibitors are considered first-line therapies for men with ED. To help physicians maximise the likelihood of treatment success with these agents, we conducted an English-language PubMed search of articles involving approved PDE5 inhibitors dating from 1 January 1998 (the year in which sildenafil citrate was introduced), through 31 August 2008. In addition to sildenafil, tadalafil and vardenafil, search terms included ‘adhere*’, ‘couple*’, ‘effect*’, ‘effic*’, ‘partner*’, ‘satisf*’, ‘succe*’ and ‘treatment outcome.’ Based on our analysis, physician activities to promote favourable treatment outcomes may be captured under the mnemonic ‘EPOCH’: (i) Evaluating and educating patients and partners to ensure realistic expectations of therapy; (ii) Prescribing a treatment individualised to the couple’s lifestyle needs and other preferences; (iii) Optimising treatment outcomes by scheduling follow-up visits with the patient to ‘fine-tune’ dosages and revisit key educational messages; (iv) Controlling comorbidities via lifestyle counselling, medications and/or referrals and (v) Helping patients and their partners to meet their health and psychosocial needs, potentially referring them to a specialist for other forms of therapy if they are not satisfied with PDE5 inhibitors. PMID:19624789

  7. Adherence to Phosphodiesterase Type 5 Inhibitors in the Treatment of Erectile Dysfunction in Long-Term Users: How Do Men Use the Inhibitors?

    PubMed Central

    Carvalheira, Ana; Forjaz, Vera; Pereira, Nuno Monteiro

    2014-01-01

    Introduction The high effectiveness of phosphodiesterase type 5 inhibitors (PDE5-i) in the treatment of erectile dysfunction (ED) has been demonstrated. However, previous research shows that PDE5-i treatments have high discontinuation rates. Aim The main goals of this study were to (i) characterize the way men use PDE5-i and (ii) analyze the adherence to treatment, identifying the factors that influence PDE5-i use. Methods A total of 148 men with clinical diagnosis for ED who maintained the treatment with PDE5-i for over 3 years were interviewed. Interviews concerning their ongoing treatment were carried out using a standardized questionnaire with quantitative and qualitative items. Main Outcome Measures Physiological measures included the intracavernous alprostadil injection test, associated with penile rigidometry and penile Doppler ultrasound. The qualitative measure included two questions: “Do you use the drug in every sexual intercourse?” and “How do you use the inhibitor?” Results ED causes were classified as venogenic (31%), arteriogenic (23%), psychogenic (18%), iatrogenic (13%), neurogenic (8%), and diabetic (7%). Participation rate was 71.8%. Of the 148 patients studied, 75% claimed not to use PDE5-i in every intercourse. Most used tadalafil (66%), followed by sildenafil (20%), vardenafil (10%), and 4% alternated the type of medicine. Four main categories emerged concerning the factors that determine the intake of PDE5-i in some intercourse situations and not in others: (i) psychological factors; (ii) medication-related factors; (iii) circumstantial factors; and (iv) relational factors. Conclusion The analysis of men's narratives revealed a combination of factors that influence the adherence to PDE5-i. The psychological and medication-related factors were the most prevalent. This study highlighted the importance of taking these factors into account, both at the time of prescription and during the follow-up in order to improve adherence

  8. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments

    PubMed Central

    Keravis, Thérèse; Lugnier, Claire

    2012-01-01

    Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene-related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways. Therefore, the investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies. This manuscript (i) overviews the different PDEs including their endogenous regulations and their specific inhibitors; (ii) analyses the intracellular implications of PDEs in regulating signalling cascades in pathogenesis, exemplified by two diseases affecting cell cycle and proliferation; and (iii) discusses perspectives for future therapeutic developments. PMID:22014080

  9. Phosphodiesterase 10A inhibitor MP-10 effects in primates: Comparison with risperidone and mechanistic implications

    PubMed Central

    Uthayathas, Subramaniam; Masilamoni, Gunasingh J.; Shaffer, Christopher L.; Schmidt, Christopher J.; Menniti, Frank S.; Papa, Stella M.

    2013-01-01

    Phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium spiny neurons of both the direct and indirect output pathways. Similar to dopamine D2 receptor antagonists acting on indirect pathway neurons, PDE10A inhibitors have shown behavioral effects in rodent models that predict antipsychotic efficacy. These findings have supported the clinical investigation of PDE10A inhibitors as a new treatment for schizophrenia. However, PDE10A inhibitors and D2 antagonists differ in effects on direct pathway and other neurons of the basal ganglia, indicating that these two drug classes may have divergent antipsychotic efficacy and side effect profile. In the present study, we compare the behavioral effects of the selective PDE10A inhibitor MP-10 to those of the clinical standard D2 antagonist risperidone in rhesus monkeys using a standardized motor disability scale for parkinsonian primates and a newly designed “Drug Effects on Nervous System” scale to assess non-motor effects. Behavioral effects of MP-10 correlated with its plasma levels and its regulation of metabolic activity in striatal and cortical regions as measured by FDG-PET imaging. While MP-10 and risperidone broadly impacted similar behavioral domains in the primate, their effects had a different underlying basis. MP-10-treated animals retained the ability to respond but did not engage tasks, whereas risperidone-treated animals retained the motivation to respond but were unable to perform the intended actions. These findings are discussed in light of what is currently known about the modulation of striatal circuitry by these two classes of compounds, and provide insight into interpreting emerging clinical data with PDE10A inhibitors for the treatment of psychotic symptoms. PMID:24490227

  10. Characterization of Binding and Inhibitory Properties of TAK-063, a Novel Phosphodiesterase 10A Inhibitor

    PubMed Central

    Harada, Akina; Suzuki, Kazunori; Kamiguchi, Naomi; Miyamoto, Maki; Tohyama, Kimio; Nakashima, Kosuke; Taniguchi, Takahiko; Kimura, Haruhide

    2015-01-01

    Phosphodiesterase 10A (PDE10A) inhibition is a novel and promising approach for the treatment of central nervous system disorders such as schizophrenia and Huntington’s disease. A novel PDE10A inhibitor, TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one] has shown high inhibitory activity and selectivity for human recombinant PDE10A2 in vitro; the half-maximal inhibitory concentration was 0.30 nM, and selectivity over other phosphodiesterases (PDEs) was more than 15000-fold. TAK-063 at 10 µM did not show more than 50% inhibition or stimulation of 91 enzymes or receptors except for PDEs. In vitro autoradiography (ARG) studies using rat brain sections revealed that [3H]TAK-063 selectively accumulated in the caudate putamen (CPu), nucleus accumbens (NAc), globus pallidus, substantia nigra, and striatonigral projection, where PDE10A is highly expressed. This [3H]TAK-063 accumulation was almost entirely blocked by an excess amount of MP-10, a PDE10A selective inhibitor, and the accumulation was not observed in brain slices of Pde10a-knockout mice. In rat brain sections, [3H]TAK-063 bound to a single high-affinity site with mean ± SEM dissociation constants of 7.2 ± 1.2 and 2.6 ± 0.5 nM for the CPu and NAc shell, respectively. Orally administered [14C]TAK-063 selectively accumulated in PDE10A expressing brain regions in an in vivo ARG study in rats. Striatal PDE10A occupancy by TAK-063 in vivo was measured using T-773 as a tracer and a dose of 0.88 mg/kg (p.o.) was calculated to produce 50% occupancy in rats. Translational studies with TAK-063 and other PDE10A inhibitors such as those presented here will help us better understand the pharmacological profile of this class of potential central nervous system drugs. PMID:25815469

  11. The role of phosphodiesterase-5 inhibitors in prostatic inflammation: a review.

    PubMed

    Peixoto, Christina Alves; Gomes, Fabiana Oliveira Dos Santos

    2015-01-01

    Clinical and basic experimental evidence indicates that chronic inflammation is the greatest factor in benign prostatic hyperplasia (BPH) progression, which is the most common cause of Lower Urinary Tract Symptoms (LUTS). The use of anti-inflammatory agents such as steroids, cyclooxygenase-2 (COX-2) and phytotherapics have been investigated as forms of treatment for various prostate diseases. Recent evidence has demonstrated that PDE5 inhibitors (PDE5Is) improve symptoms of BPH/LUTS, possibly as a result of the relaxing of the smooth muscle fibers of the bladder and prostate by NO/cGMPc signaling, or by improving RhoA/Rho-kinase (ROCK), and reduction of the hyperactivity of the autonomic nervous system. However, some results have suggested that besides vasodilatation and their anti-proliferative effect, PDE5Is exert a direct anti-inflammatory effect, by raising cGMP. Given that inflammation is major factor in benign prostatic hyperplasia (BPH) progression, PDE5Is could act also restore prostatic function as they act as potent anti-inflammatory drugs. This review aims to provide a comprehensive summary of the use of phosphodiesterase-5 inhibitors to treat prostatic inflammation. PMID:26379476

  12. Structural basis for the design of selective phosphodiesterase 4B inhibitors.

    PubMed

    Fox, David; Burgin, Alex B; Gurney, Mark E

    2014-03-01

    Phosphodiesterase-4B (PDE4B) regulates the pro-inflammatory Toll Receptor -Tumor Necrosis Factor α (TNFα) pathway in monocytes, macrophages and microglial cells. As such, it is an important, although under-exploited molecular target for anti-inflammatory drugs. This is due in part to the difficulty of developing selective PDE4B inhibitors as the amino acid sequence of the PDE4 active site is identical in all PDE4 subtypes (PDE4A-D). We show that highly selective PDE4B inhibitors can be designed by exploiting sequence differences outside the active site. Specifically, PDE4B selectivity can be achieved by capture of a C-terminal regulatory helix, now termed CR3 (Control Region 3), across the active site in a conformation that closes access by cAMP. PDE4B selectivity is driven by a single amino acid polymorphism in CR3 (Leu674 in PDE4B1 versus Gln594 in PDE4D). The reciprocal mutations in PDE4B and PDE4D cause a 70-80 fold shift in selectivity. Our structural studies show that CR3 is flexible and can adopt multiple orientations and multiple registries in the closed conformation. The new co-crystal structure with bound ligand provides a guide map for the design of PDE4B selective anti-inflammatory drugs. PMID:24361374

  13. Icariside II, a novel phosphodiesterase-5 inhibitor, attenuates streptozotocin-induced cognitive deficits in rats.

    PubMed

    Yin, Caixia; Deng, Yuanyuan; Gao, Jianmei; Li, Xiaohui; Liu, Yuangui; Gong, Qihai

    2016-07-22

    Beta-amyloid (Aβ) deposition and neuroinflammation are involved in Alzheimer's disease (AD)-type neurodegeneration with cognitive deficits. Phosphodiesterase-5 (PDE5) inhibitors have recently been studied as a potential target for cognitive enhancement by reducing inflammatory responses and Aβ levels. The present study was designed to investigate the effects of icariside II (ICS II), a novel PDE5 inhibitor derived from the traditional Chinese herb Epimedium brevicornum, on cognitive deficits, Aβ levels and neuroinflammation induced by intracerebroventricular-streptozotocin (ICV-STZ) in rats. The results demonstrated that ICV-STZ exhibited cognitive deficits and neuronal morphological damage, along with Aβ increase and neuroinflammation in the rat hippocampus. ICS II improved cognitive deficits, attenuated neuronal death, and decreased the levels of Aβ1-40, Aβ1-42 and PDE5 in the hippocampus of STZ rats. Furthermore, administration of ICS II at the dose of 10mg/kg for 21days significantly suppressed the expression of beta-amyloid precursor protein (APP), beta-secretase1 (BACE1) and increased the expressions of neprilysin (NEP) together with inhibited interleukin-1β (IL-1β), tumor necrosis factor (TNF)-α, cyclooxygenase-2 (COX-2) and transforming growth factor-β1 (TGF-β1) levels. In addition, ICS II exerted a beneficial effect on inhibition of IκB-α degradation and NF-κB activation induced by STZ. Taken together, the present study demonstrated that ICS II was a potential therapeutic agent for AD treatment. PMID:27109920

  14. Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294.

    PubMed

    Gale, Donna D; Hofer, Peter; Spina, Domenico; Seeds, Esther A; Banner, Katherine H; Harrison, Selina; Douglas, Gary; Matsumoto, Tatsui; Page, Clive P; Wong, Richard H; Jordan, Stephan; Smith, Forrest; Banik, Nandini; Halushka, Perry V; Cavalla, David; Rotshteyn, Yakov; Kyle, Donald J; Burch, Ronald M; Chasin, Mark

    2003-01-01

    V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC(50) for PDE4. In contrast, rolipram induced severe retching and vomiting at 10 mg/kg, p.o. In conclusion, V11294 is an orally active PDE4 inhibitor that exhibits antiinflammatory activity in vitro, and in vivo at doses that are not emetogenic. PMID:12670778

  15. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma

    PubMed Central

    2010-01-01

    GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics. Methods In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR. Results GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p = 0.007) and 34.3% (p = 0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p = 0.014) and 57.2% (p = 0.014) respectively compared to placebo. There was no effect on pre-allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects. Conclusions GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma. Trial Registration This study is registered on clinicaltrials.gov NCT00380354 PMID:20193079

  16. Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

    PubMed

    Raheem, Izzat T; Schreier, John D; Fuerst, Joy; Gantert, Liza; Hostetler, Eric D; Huszar, Sarah; Joshi, Aniket; Kandebo, Monika; Kim, Somang H; Li, Jing; Ma, Bennett; McGaughey, Georgia; Sharma, Sujata; Shipe, William D; Uslaner, Jason; Vandeveer, George H; Yan, Youwei; Renger, John J; Smith, Sean M; Coleman, Paul J; Cox, Christopher D

    2016-01-01

    Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer. PMID:26602277

  17. Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction

    PubMed Central

    Ückert, Stefan; Oelke, Matthias

    2011-01-01

    Several disorders of the human upper and lower urinary tract, such as urinary stone disease, lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and detrusor overactivity, can be therapeutically addressed by influencing the function of the smooth musculature of the ureter, prostate or urinary bladder, respectively. In order to ensure a drug effect without significant adverse events, a certain degree of tissue selectivity is mandatory. The treatment of said conditions aims to focus on orally available drugs acting via intracellular signalling pathways. Specifically, the cyclic nucleotide monophosphate cyclic GMP represents an important mediator in the control of the outflow region (bladder, urethra). The use of phosphodiesterase (PDE) inhibitors, such as sildenafil, tadalafil, vardenafil, avanafil or udenafil, known to restrain the degradation of the second messenger cyclic GMP, offers great opportunities in the treatment of lower urinary tract dysfunction. PDE inhibitors are regarded as efficacious, have a rapid onset of action and favourable effect-to-side-effect ratio. The role of PDE5 inhibitors in the treatment of BPH/LUTS and the overactive bladder has already been addressed in randomized, double-blind, placebo-controlled trials, as well as preliminary open-label studies enrolling either several hundreds or only 20 patients. The purpose of this review is to focus on the potential use and clinical significance of PDE inhibitors in the treatment of storage and voiding dysfunctions of the lower urinary tract. The strategy of modulating the activity of PDE isoenzymes might represent a novel approach in patients with lower urinary tract dysfunction (LUTD). PMID:21745238

  18. Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity

    PubMed Central

    Wang, Huanchen; Yan, Zier; Yang, Serena; Cai, Jiwen; Robinson, Howard; Ke, Hengming

    2009-01-01

    Cyclic nucleotide phosphodiesterase-8 (PDE8) is a family of cAMP-specific enzymes and plays important roles in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia, and thyroid function. However, no PDE8 selective inhibitors are available for trial treatment of human diseases. Here we report kinetic properties of the highly active PDE8A1 catalytic domain prepared from refolding and its crystal structures in the unliganded and 3-isobutyl-1-methylxanthine (IBMX) bound forms at 1.9 and 2.1 Å resolutions, respectively. The PDE8A1 catalytic domain has KM of 1.8 μM, Vmax of 6.1 μmol/min/mg, kcat of 4.0 s−1 for cAMP, and KM of 1.6 mM, Vmax of 2.5 μmol/min/mg, kcat of 1.6 s−1 for cGMP, thus indicating that the substrate specificity of PDE8 is dominated by KM. The structure of the PDE8A1 catalytic domain has similar topology as those of other PDE families, but contains two extra helices around Asn685-Thr710. Since this fragment is distant from the active site of the enzyme, its impact on the catalysis is unclear. The PDE8A1 catalytic domain is insensitive to the IBMX inhibition (IC50 = 700 μM). The unfavorable interaction of IBMX in the PDE8A1-IBMX structure suggests an important role of Tyr748 in the inhibitor binding. Indeed, the mutation of Tyr748 to phenylalanine increases the PDE8A1 sensitivity to several non-selective or family-selective PDE inhibitors. Thus, the structural and mutagenesis studies provide not only insight into the enzymatic properties, but also guidelines for design of PDE8 selective inhibitors. PMID:18983167

  19. Kinetic and Structural Studies of Phosphodiesterase-8A and Implication on the Inhibitor Selectivity

    SciTech Connect

    Wang, H.; Yan, Z; Yang, S; Cai, J; Robinson, H; Ke, H

    2008-01-01

    Cyclic nucleotide phosphodiesterase-8 (PDE8) is a family of cAMP-specific enzymes and plays important roles in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia, and thyroid function. However, no PDE8 selective inhibitors are available for trial treatment of human diseases. Here we report kinetic properties of the highly active PDE8A1 catalytic domain prepared from refolding and its crystal structures in the unliganded and 3-isobutyl-1-methylxanthine (IBMX) bound forms at 1.9 and 2.1 Angstroms resolutions, respectively. The PDE8A1 catalytic domain has a KM of 1.8 eM, Vmax of 6.1 emol/min/mg, a kcat of 4.0 s-1 for cAMP, and a KM of 1.6 mM, Vmax of 2.5 emol/min/mg, a kcat of 1.6 s-1 for cGMP, thus indicating that the substrate specificity of PDE8 is dominated by KM. The structure of the PDE8A1 catalytic domain has similar topology as those of other PDE families but contains two extra helices around Asn685-Thr710. Since this fragment is distant from the active site of the enzyme, its impact on the catalysis is unclear. The PDE8A1 catalytic domain is insensitive to the IBMX inhibition (IC50 = 700 eM). The unfavorable interaction of IBMX in the PDE8A1-IBMX structure suggests an important role of Tyr748 in the inhibitor binding. Indeed, the mutation of Tyr748 to phenylalanine increases the PDE8A1 sensitivity to several nonselective or family selective PDE inhibitors. Thus, the structural and mutagenesis studies provide not only insight into the enzymatic properties but also guidelines for design of PDE8 selective inhibitors.

  20. In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor.

    PubMed

    Nials, Anthony T; Tralau-Stewart, Cathy J; Gascoigne, Michele H; Ball, Douglas I; Ranshaw, Lisa E; Knowles, Richard G

    2011-04-01

    Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical and clinical investigation of inhaled PDE4 inhibitors is ongoing. 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066) is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery. The aim of these studies was to investigate the potency, duration of action, and therapeutic index of GSK256066 in animal models of pulmonary inflammation. The effects of intratracheally administered GSK256066 were investigated in rat lipopolysaccharide (LPS)- and ovalbumin (OVA)-induced models of acute pulmonary inflammation. In some studies, fluticasone propionate (FP) was included as a comparator. The therapeutic index (anti-inflammatory effect versus emesis) of GSK256066 was studied in ferrets where acute pulmonary inflammation was induced with inhaled LPS. In rats, GSK256066 and FP caused significant (p < 0.05) inhibition of LPS-induced pulmonary neutrophilia. The duration of action of GSK256066 at 10 × ED(50) dose (10 μg/kg) was 12 h. GSK256066 and FP also inhibited LPS-induced increases in exhaled nitric oxide (ED(50) 35 and 92 μg/kg, respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats exposed to OVA (ED(50) 0.4 μg/kg). In ferrets, inhaled GSK256066 inhibited LPS-induced pulmonary neutrophilia (ED(50) 18 μg/kg), and no emetic episodes were observed. Thus, GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast. In summary, GSK256066 demonstrates potent and long-lasting anti-inflammatory effects in animal models of pulmonary inflammation and does not induce emetic episodes in ferrets. GSK256066 has potential as an inhaled therapeutic for the treatment of asthma and chronic obstructive pulmonary disease. PMID:21205924

  1. Phosphodiesterase Type 5 Inhibitors Increase Herceptin Transport and Treatment Efficacy in Mouse Metastatic Brain Tumor Models

    PubMed Central

    Inoue, Satoshi; Konda, Bindu; Patil, Rameshwar; Ding, Hui; Espinoza, Andres; Wawrowsky, Kolja A.; Patil, Chirag; Ljubimov, Alexander V.; Black, Keith L.

    2010-01-01

    Background Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment. Methodology/Principal Findings We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [14C]dextran and trastuzumab (Herceptin®, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [14C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05). Conclusions

  2. The devil is in the details: an analysis of the subtleties between phosphodiesterase inhibitors for erectile dysfunction

    PubMed Central

    Smith-Harrison, L.I.; Patel, Abhishek

    2016-01-01

    Erectile dysfunction (ED) is a common sexual disorder with numerous etiologies involving multiple organ systems that leads to significant distress and decreased quality of life for the affected men. Fortunately, there are several modalities and interventions for treating ED. Oral medications, intra-urethral compounds, intracorporeal injections, vacuum-assist devices and surgically implanted prostheses are all part of the treatment algorithm. One of the first-lines and certainly the most widely used options for treating ED is the family of oral phosphodiesterase type 5 inhibitors (PDE5I). The introduction of these medications in the late 1990s revolutionized the field of sexual medicine. Currently there are no guidelines and minimal literature to help providers choose among drugs in this class. This review will address differences in efficacy and side effects between various members of the oral selective phosphodiesterase-5 inhibitor class of drugs. PMID:27141444

  3. The devil is in the details: an analysis of the subtleties between phosphodiesterase inhibitors for erectile dysfunction.

    PubMed

    Smith-Harrison, L I; Patel, Abhishek; Smith, Ryan P

    2016-04-01

    Erectile dysfunction (ED) is a common sexual disorder with numerous etiologies involving multiple organ systems that leads to significant distress and decreased quality of life for the affected men. Fortunately, there are several modalities and interventions for treating ED. Oral medications, intra-urethral compounds, intracorporeal injections, vacuum-assist devices and surgically implanted prostheses are all part of the treatment algorithm. One of the first-lines and certainly the most widely used options for treating ED is the family of oral phosphodiesterase type 5 inhibitors (PDE5I). The introduction of these medications in the late 1990s revolutionized the field of sexual medicine. Currently there are no guidelines and minimal literature to help providers choose among drugs in this class. This review will address differences in efficacy and side effects between various members of the oral selective phosphodiesterase-5 inhibitor class of drugs. PMID:27141444

  4. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease

    PubMed Central

    Rabe, Klaus F

    2011-01-01

    Phosphodiesterase 4 (PDE4) is a member of the PDE enzyme superfamily that inactivates cyclic adenosine monophosphate and cyclic guanosine monophosphate, and is the main PDE isoenzyme occurring in cells involved in inflammatory airway disease such as chronic obstructive pulmonary disease (COPD). COPD is a preventable and treatable disease and is characterized by airflow obstruction that is not fully reversible. Chronic progressive symptoms, particularly dyspnoea, chronic bronchitis and impaired overall health are worse in those who have frequent, acute episodes of symptom exacerbation. Although several experimental PDE4 inhibitors are in clinical development, roflumilast, a highly selective PDE4 inhibitor, is the first in its class to be licensed, and has recently been approved in several countries for oral, once-daily treatment of severe COPD. Clinical trials have demonstrated that roflumilast improves lung function and reduces exacerbation frequency in COPD. Furthermore, its unique mode of action may offer the potential to target the inflammatory processes underlying COPD. Roflumilast is effective when used concomitantly with all forms of bronchodilator and even in patients treated with inhaled corticosteroids. Roflumilast thus represents an important addition to current therapeutic options for COPD patients with chronic bronchitis, including those who remain symptomatic despite treatment. This article reviews the current status of PDE4 inhibitors, focusing on the pharmacokinetics, efficacy and safety of roflumilast. In particular, it provides an overview of the effects of roflumilast on lung function and exacerbations, glucose homoeostasis and weight loss, and the concomitant use of long-acting beta2-adrenergic receptor agonists and short-acting muscarinic receptor antagonists. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID

  5. Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors.

    PubMed

    Rafael, Adilia; Torres, Tiago

    2016-01-01

    Psoriasis is a common, chronic and disabling skin disorder affecting approximately 2% of the population, associated with significant negative impact on the patient's quality of life. Approximately 80% of those affected with psoriasis have mild-to-moderate forms and are usually treated with topical therapy, whereas phototherapy and systemic therapies are used for those with severe disease. In the past three decades, the major advances in psoriasis therapy have been in systemic agents for the treatment of moderate-to-severe psoriasis, particularly new immunomodulatory and biological molecules, while topical therapies have remained relatively unchanged over the past decades. Indeed, topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis. Thus, there is a need to develop new and more effective topical agents in the short and long term, with a better efficacy and safety profile than corticosteroids and vitamin D3 analogs. Over the past five years, investigation into topical therapy has expanded, with exciting new drugs being developed. Preliminary results of these emerging agents that selectively target disease-defining pathogenic pathways seem to be promising, although long-term and large-scale studies assessing safety and efficacy are still lacking. The aim of this article was to review the clinical and research data of some emerging topical agents, focusing on Janus kinase-signal transducer and activator of transcription and phosphodiesterase type 4 inhibitors, which are currently being investigated. PMID:26552963

  6. Phosphodiesterase 5 inhibitors prevent 3,4-methylenedioxymethamphetamine-induced 5-HT deficits in the rat.

    PubMed

    Puerta, Elena; Hervias, Isabel; Goñi-Allo, Beatriz; Lasheras, Berta; Jordan, Joaquin; Aguirre, Norberto

    2009-02-01

    Phosphodiesterase 5 (PDE5) inhibitors are often used in combination with club drugs such as 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). We investigated the consequences of such combination in the serotonergic system of the rat. Oral administration of sildenafil citrate (1.5 or 8 mg/kg) increased brain cGMP levels and protected in a dose-dependent manner against 5-hydroxytryptamine depletions caused by MDMA (3 x 5 mg/kg, i.p., every 2 h) in the striatum, frontal cortex and hippocampus without altering the acute hyperthermic response to MDMA. Intrastriatal administration of the protein kinase G (PKG) inhibitor, KT5823 [(9S, 10R, 12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, methyl ester)], suppressed sildenafil-mediated protection. By contrast, the cell permeable cGMP analogue, 8-bromoguanosine cyclic 3',5'-monophosphate, mimicked sildenafil effects further suggesting the involvement of the PKG pathway in mediating sildenafil protection. Because mitochondrial ATP-sensitive K(+) channels are a target for PKG, we next administered the specific mitochondrial ATP-sensitive K(+) channel blocker, 5-hydroxydecanoic acid, 30 min before sildenafil. 5-hydroxydecanoic acid completely reversed the protection afforded by sildenafil, thereby implicating the involvement of mitochondrial ATP-sensitive K(+) channels. Sildenafil also increased Akt phosphorylation, and so the possible involvement of the Akt/endothelial nitric oxide synthase (eNOS)/sGC signalling pathway was analysed. Neither the phosphatidylinositol 3-kinase inhibitor, wortmannin, nor the selective eNOS inhibitor, L-N5-(1-iminoethyl)-L-ornithine dihydrochloride, reversed the protection afforded by sildenafil, suggesting that Akt/eNOS/sGC cascade does not participate in the protective mechanisms. Our data also show that the protective effect of sildenafil can be extended to vardenafil, another PDE5

  7. Modulation of eotaxin formation and eosinophil migration by selective inhibitors of phosphodiesterase type 4 isoenzyme.

    PubMed

    Silva, P M; Alves, A C; Serra, M F; Pires, A L; Silva, J P; Barreto, E O; Cordeiro, R S; Jose, P J; Teixeira, M M; Lagente, V; Martins, M A

    2001-09-01

    1. This study was undertaken to investigate the possible contribution of the blockade of eotaxin generation to the anti-eosinophilotactic effect of phosphodiesterase (PDE) type 4 inhibitors. In some experiments, the putative synergistic interaction between PDE type 4 inhibitors and the beta2-agonist salbutamol was also assessed. 2. Sensitized guinea-pigs aerosolized with antigen (5% ovalbumin, OVA) responded with a significant increase in eotaxin and eosinophil levels in the bronchoalveolar lavage fluid (BALF) at 6 h. Eosinophil recruitment was inhibited by both PDE type 4 inhibitors rolipram (5 mg kg(-1), i.p.) and RP 73401 (5 mg kg(-1), i.p.) treatments. In contrast, only rolipram inhibited eotaxin production. 3. Sensitized rats intrapleurally challenged (i.pl.) with antigen (OVA, 12 microg cavity(-1)) showed a marked eosinophil infiltration at 24 h, preceded by eotaxin generation at 6 h. Intravenous administration of a rabbit anti-mouse eotaxin antibody (0.5 mg kg(-1)) significantly reduced allergen-evoked eosinophilia in this model. 4. Local pretreatment with rolipram (40 microg cavity(-1)) or RP 73401 (40 microg cavity(-1)) 1 h before challenge reduced eosinophil accumulation evaluated in the rat pleural effluent, but only the former was active against eotaxin generation. The inhibitors of PDE type 3 (SK&F 94836) and type 5 (zaprinast) failed to alter allergen-evoked eosinophil recruitment in rats. 5. Local injection of beta2-agonist salbutamol (20 microg cavity(-1)) inhibited both eosinophil accumulation and eotaxin production following pleurisy. The former was better inhibited when salbutamol and rolipram were administered in combination. 6. Treatment with rolipram and RP 73401 dose-dependently inhibited eosinophil adhesion and migration in vitro. These effects were clearly potentiated by salbutamol at concentrations that had no effect alone. 7. Our findings indicate that although rolipram and RP 73401 are equally effective in inhibiting allergen

  8. Patient preference and satisfaction in erectile dysfunction therapy: a comparison of the three phosphodiesterase-5 inhibitors sildenafil, vardenafil and tadalafil

    PubMed Central

    Raheem, Amr Abdel; Kell, Philip

    2009-01-01

    Erectile dysfunction (ED) is a problem that may affect up to 52% of men between the ages of 40 and 70. It can be distressing because of its negative effect on self-esteem, quality of life, and interpersonal relationships. Oral phosphodiesterase-5 inhibitors (PDE5 inhibitors) are now the first choice of treatment in ED. The availability of three (sildenafil citrate, tadalafil, and vardenafil) well tolerated and effective oral PDE5 inhibitors gives treatment options for men with ED. Although the mechanism of action is the same for the three drugs, they differ in their pharmacokinetics. Several preference studies were conducted between the three PDE5 inhibitors but they were not free from bias. Because of the lack of overwhelming reliable data showing that one PDE5 inhibitor is superior to another, current opinion is that the individual patient should have the opportunity to test all three drugs and then select the one that best suits him and his partner. PMID:19936151

  9. Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update.

    PubMed

    Zhang, Wen-Hao; Zhang, Xin-Hua

    2016-01-01

    Phosphodiesterase isoenzymes 5 inhibitors (PDE5-Is) are the first-line therapy for erectile dysfunction (ED). The constant discoveries of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cell-signaling pathway for smooth muscle (SM) control in other urogenital tracts (UGTs) make PDE5-Is promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-Is have been widely recognized. On-demand PDE5-Is are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase (sGC) stimulators also have promising role in the management of severe ED conditions. PDE5-Is are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-Is, especially combined with α-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia (BPH) except on maximum urinary flow rate (Q max ) with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-Is are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie's disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-Is in disorders of UGTs are required. PMID:26620458

  10. The role of cilostazol, a phosphodiesterase 3 inhibitor, on oocyte maturation and subsequent pregnancy in mice.

    PubMed

    Li, Min; Yu, Yang; Yan, Jie; Yan, Li-Ying; Zhao, Yue; Li, Rong; Liu, Ping; Hsueh, Aaron J; Qiao, Jie

    2012-01-01

    It is important to identify effective contraceptive drugs that cause minimal disruption to physiological processes. Phosphodiesterase 3 (PDE3) inhibitors suppress meiosis in oocytes by decreasing the level of cAMP and blocking the extrusion of the first polar body. In this study, we tested the PDE3 inhibitor, cilostazol, as a potential contraceptive agent. The effects of cilostazol treatment in vitro and in vivo on the suppression of oocyte maturation in a mouse model were investigated. The results indicated that treatment with increasing concentrations of cilostazol led to a dose-dependent arrest in meiosis progression. The effective in vitro concentration was 1 µM and was 300 mg/kg in vivo. The effect of cilostazol was reversible. After removal of the drug, meiosis resumed and mouse oocytes matured in vitro, and showed normal chromosome alignment and spindle organization. After fertilization using an ICSI method, the oocytes showed normal morphology, fertilization rate, embryo cleavage, blastocyst formation, and number of viable pups when compared with controls. The offspring showed similar body weight and fertility. In vivo, the mice became infertile if the drug was injected sequentially, and became pregnant following discontinuation of cilostazol. More importantly, no side effects of cilostazol were observed in treated female mice as demonstrated by blood pressure and heart rate monitoring. It is concluded that cilostazol, a drug routinely used for intermittent claudication, can effectively inhibit oocyte maturation in vitro and in vivo, does not affect the developmental potential of oocytes following drug removal and has few side effects in female mice treated with this drug. These findings suggest that cilostazol may be a potential new contraceptive agent that may facilitate an efficacy and safety study of this drug. PMID:22292006

  11. Application of neurophysiological biomarkers for Huntington's disease: evaluating a phosphodiesterase 9A inhibitor.

    PubMed

    Nagy, Dávid; Tingley, Francis D; Stoiljkovic, Milan; Hajós, Mihály

    2015-01-01

    Several neurophysiological abnormalities have been described in Huntington's disease, including auditory gating deficit, which are considered to reflect impaired brain information-processing. Since transgenic animal models of Huntington's disease capture basic neuropathology of the disorder, auditory gating was studied in BACHD (line5) transgenic rats and Q175 transgenic mice, together with local field gamma power in the hippocampus and primary auditory cortex. Using clinically equivalent acoustic-stimulation paradigms, impaired auditory gating was detected in transgenic BACHD rats under anesthesia and in freely-moving condition. In addition, transgenic BACHD rats showed a lower level of hippocampal and cortical field gamma band power compared to wild-type counterpart, which might be related to their compromised mitochondrial function. Systemic administration of the recently developed phosphodiesterase 9A (PDE9A) inhibitor PF-04447943 dose-dependently improved gating deficit in transgenic BACHD rats in both brain regions. Q175 mice, including wild-type, heterozygote and homozygote mice showed similarly poor gating, and administration of PF-04447943 was without effect. Treatment of transgenic BACHD rats with daily administration of PF-04447943 (1mg/kg) over 7-days resulted in an improvement in their auditory gating both in the hippocampus and primary auditory cortex as evaluated 24h after the last treatment. In fact, differences in auditory gating between wild-type and transgenic BACHD rats were totally abolished after sub-chronic treatment with the PDE9A inhibitor. Our findings indicate that BACHD transgenic rats show abnormal auditory gating with features resembling those of Huntington's disease patients, which could be considered as potential translational biomarker for drug development in treatment of this disease. PMID:25315303

  12. Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update

    PubMed Central

    Zhang, Wen-Hao; Zhang, Xin-Hua

    2016-01-01

    Phosphodiesterase isoenzymes 5 inhibitors (PDE5-Is) are the first-line therapy for erectile dysfunction (ED). The constant discoveries of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cell-signaling pathway for smooth muscle (SM) control in other urogenital tracts (UGTs) make PDE5-Is promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-Is have been widely recognized. On-demand PDE5-Is are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase (sGC) stimulators also have promising role in the management of severe ED conditions. PDE5-Is are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-Is, especially combined with α-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia (BPH) except on maximum urinary flow rate (Qmax) with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-Is are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie's disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-Is in disorders of UGTs are required. PMID:26620458

  13. Anxiolytic Effects of Phosphodiesterase-2 Inhibitors Associated with Increased cGMP Signaling

    PubMed Central

    Masood, Anbrin; Huang, Ying; Hajjhussein, Hassan; Xiao, Lan; Li, Hao; Wang, Wei; Hamza, Adel; Zhan, Chang-Guo

    2009-01-01

    Phosphodiesterase (PDE)-2 is a component of the nitric-oxide synthase (NOS)/guanylyl cyclase signaling pathway in the brain. Given recent evidence that pharmacologically induced changes in NO-cGMP signaling can affect anxiety-related behaviors, the effects of the PDE2 inhibitors (2-(3,4-dimethoxybenzyl)-7-det-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one) (Bay 60-7550) and 3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzamide (ND7001), as well as modulators of NO, were assessed on cGMP signaling in neurons and on the behavior of mice in the elevated plus-maze, hole-board, and open-field tests, well established procedures for the evaluation of anxiolytics. Bay 60-7550 (1 μM) and ND7001 (10 μM) increased basal and N-methyl-d-aspartate- or detanonoate-stimulated cGMP in primary cultures of rat cerebral cortical neurons; Bay 60-7550, but not ND7001, also increased cAMP. Increased cGMP signaling, either by administration of the PDE2 inhibitors Bay 60-7550 (0.5, 1, and 3 mg/kg) or ND7001 (1 mg/kg), or the NO donor detanonoate (0.5 mg/kg), antagonized the anxiogenic effects of restraint stress on behavior in the three tests. These drugs also produced anxiolytic effects on behavior in nonstressed mice in the elevated plus-maze and hole-board tests; these effects were antagonized by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (20 mg/kg). By contrast, the NOS inhibitor Nω-nitro-l-arginine methyl ester (50 mg/kg), which reduces cGMP signaling, produced anxiogenic effects similar to restraint stress. Overall, the present behavioral and neurochemical data suggest that PDE2 may be a novel pharmacological target for the development of drugs for the treatment of anxiety disorders. PMID:19684253

  14. Sildenafil, a phosphodiesterase type 5 inhibitor, attenuates diabetic nephropathy in non-insulin-dependent Otsuka Long-Evans Tokushima Fatty rats

    PubMed Central

    Kuno, Yoshihiro; Iyoda, Masayuki; Shibata, Takanori; Hirai, Yuki; Akizawa, Tadao

    2011-01-01

    BACKGROUND It is well established that the pathogenesis of diabetic nephropathy is associated with abnormalities of renal nitric oxide (NO) generation. Many of the biological actions of NO are mediated by cGMP, which is rapidly degraded by phosphodiesterases. In this study, we evaluated the renoprotective effects of sildenafil (SIL), an inhibitor of phosphodiesterase-5, in type 2 diabetic rats. METHODS Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent diabetes model, and Long-Evans Tokushima Otsuka rats, a non-diabetic control, were treated with either SIL (2.5 mg·kg−1 in drinking water) or undosed water for 28 weeks, starting at 30 weeks of age. RESULTS Sildenafil treatment significantly decreased albuminuria, attenuated glomerular hyperfiltration and resulted in a decrease in glomerular hypertrophy, in addition to a reduced glomerulosclerosis score and a dramatic decrease in the number of glomerular and tubulointerstitial proliferating cell nuclear antigen-positive cells in OLETF rats. This was accompanied by a significant reduction in renal cortical mRNA levels of collagen types I and III. The increased mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 in the OLETF rats were significantly or partially attenuated by SIL treatment. CONCLUSIONS This study suggests that SIL attenuated diabetic nephropathy due to its potent antiproliferative effects and its regulatory effects on extracellular matrix. This latter effect is thought to be a result of its ability to affect the balance between MMPs and their inhibitors. PMID:21133896

  15. Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram

    SciTech Connect

    Chang, Weiyuan; Chen, Jing; Schlueter, Connie F.; Rando, Roy J.; Pathak, Yashwant V.; Hoyle, Gary W.

    2012-09-01

    Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228–270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery. -- Highlights: ► Chlorine causes lung injury when inhaled and is considered a chemical threat agent. ► Rolipram inhibited chlorine-induced pulmonary edema and airway hyperreactivity. ► Post-exposure rolipram treatments by both systemic and local delivery were effective. ► Rolipram shows promise as a rescue treatment for chlorine-induced lung injury.

  16. Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

    PubMed Central

    Subbian, Selvakumar; Tsenova, Liana; Holloway, Jennifer; Peixoto, Blas; O'Brien, Paul; Dartois, Véronique; Khetani, Vikram; Zeldis, Jerome B.; Kaplan, Gilla

    2016-01-01

    Objectives Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. Methods A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. Results Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. Conclusions Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment. PMID:26981575

  17. Phosphodiesterase-5 inhibitors oppose hyperoxic vasoconstriction and accelerate seizure development in rats exposed to hyperbaric oxygen.

    PubMed

    Demchenko, Ivan T; Ruehle, Alex; Allen, Barry W; Vann, Richard D; Piantadosi, Claude A

    2009-04-01

    Oxygen is a potent cerebral vasoconstrictor, but excessive exposure to hyperbaric oxygen (HBO(2)) can reverse this vasoconstriction by stimulating brain nitric oxide (NO) production, which increases cerebral blood flow (CBF)-a predictor of O(2) convulsions. We tested the hypothesis that phosphodiesterase (PDE)-5 blockers, specifically sildenafil and tadalafil, increase CBF in HBO(2) and accelerate seizure development. To estimate changes in cerebrovascular responses to hyperoxia, CBF was measured by hydrogen clearance in anesthetized rats, either control animals or those pretreated with one of these blockers, with the NO inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME), with the NO donor S-nitroso-N-acetylpenicillamine (SNAP), or with a blocker combined with l-NAME. Animals were exposed to 30% O(2) at 1 atm absolute (ATA) ("air") or to 100% O(2) at 4 or 6 ATA. EEG spikes indicated central nervous system CNS O(2) toxicity. The effects of PDE-5 blockade varied as a positive function of ambient Po(2). In air, CBF did not increase significantly, except after pretreatment with SNAP. However, at 6 ATA O(2), mean values for CBF increased and values for seizure latency decreased, both significantly; pretreatment with l-NAME abolished these effects. Conscious rats treated with sildenafil before HBO(2) were also more susceptible to CNS O(2) toxicity, as demonstrated by significantly shortened convulsive latency. Decreases in regional CBF reflect net vasoconstriction in the brain regions studied, since mean arterial pressures remained constant or increased throughout. Thus PDE-5 blockers oppose the protective vasoconstriction that is the initial response to hyperbaric hyperoxia, decreasing the safety of HBO(2) by hastening onset of CNS O(2) toxicity. PMID:19179645

  18. Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft.

    PubMed

    Kossmann, Bradley R; Abdelmalak, Monica; Lopez, Sophia; Tender, Gabrielle; Yan, Chunli; Pommier, Yves; Marchand, Christophe; Ivanov, Ivaylo

    2016-07-15

    Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft. MM-PBSA per-residue energy decomposition identified important interactions of the compounds with specific TDP2 residues. These interactions could provide new avenues for synthetic optimization of these scaffolds. PMID:27262595

  19. Switching from Nitrate Therapy to Ranolazine in Patients with Coronary Artery Disease Receiving Phosphodiesterase Type-5 Inhibitors for Erectile Dysfunction

    PubMed Central

    Udeoji, Dioma U; Schwarz, Ernst R

    2014-01-01

    Coronary artery disease (CAD) and erectile dysfunction (ED) frequently coexist. The introduction of phosphodiesterase type-5 (PDE-5) inhibitors has revolutionized medical management of organic ED; however, in patients with angina pectoris, a common symptom of CAD, coadministration of PDE-5 inhibitors and nitrates has been implicated in CAD-related deaths following sexual activity. The mechanism of action of PDE-5 inhibitors results in a potential cumulative drop in blood pressure (BP); thus, these agents are contraindicated in patients receiving nitrates. Beta-blockers and calcium channel antagonists are considered the mainstays of antianginal therapy, but may not be tolerated by all patients. Ranolazine is an antianginal agent that produces minimal reductions in heart rate and BP. Here we report three cases of men with CAD, chronic angina, and concomitant ED. We describe our treatment approach in these patients, using ranolazine as a potential substitute to nitrate therapy. PMID:25452706

  20. Synthesis of Novel Tadalafil Analogues and their Evaluation as Phosphodiesterase Inhibitors and Anticancer Agents

    PubMed Central

    Abadi, Ashraf H.; Abouel-Ella, Dalal A.; Ahmed, Nermin S.; Gary, Bernard D.; Thaiparambil, Jose T.; Tinsley, Heather N.; Keeton, Adam B.; Piazza, Gary A.

    2016-01-01

    Two closely related series of novel β-carboline derivatives, electronically similar to tadalafil (CAS 171596-29-5), were synthesized and evaluated for their inhibitory effects upon phosphodiesterase 5 (PDE5) and phosphodiesterase 11 (PDE11) and their in vitro tumor cell growth inhibitory activity versus HT29 colorectal carcinoma cell line. Interestingly, some of the synthesized compounds showed growth inhibitory properties that appear to be associated with their ability to inhibit PDE5. Moreover, the PDE5 inhibition seems relevant to the stereochemical aspects of the compounds. PMID:19813465

  1. Sildenafil and analogous phosphodiesterase type 5 (PDE-5) inhibitors in herbal food supplements sampled on the Dutch market.

    PubMed

    Reeuwijk, N M; Venhuis, B J; de Kaste, D; Hoogenboom, L A P; Rietjens, I M C M; Martena, M J

    2013-01-01

    Herbal food supplements, claiming to enhance sexual potency, may contain deliberately added active pharmacological ingredients (APIs) that can be used for the treatment of erectile dysfunction (ED). The aim of this study was to determine whether herbal food supplements on the Dutch market indeed contain APIs that inhibit phosphodiesterase type 5 (PDE-5) inhibitors, such as sildenafil and analogous PDE-5 inhibitors. Herbal food supplements intended to enhance sexual potency (n = 71), and two soft drinks, were sampled from 2003 up to and including 2012. In 23 herbal supplements, nine different PDE-5 inhibitors were identified; in a few cases (n = 3), more than one inhibitor was indentified. The presence of these APIs was however not stated on the label. The concentrations of PDE-5 inhibitors per dose unit were analysed. Furthermore, the potential pharmacologically active properties of the detected PDE-5 inhibitors were estimated by using data from the scientific and patent literature regarding (1) in vitro PDE-5 activity, (2) reported effective doses of registered drugs with PDE-5 inhibitor activity and (3) similarity to other structural analogues. It was concluded that 18 of the 23 herbal food supplements, when used as recommended, would have significant pharmacological effects due to added APIs. Adequate use of existing regulation and control measures seems necessary to protect consumers against the adverse effects of these products. PMID:24261938

  2. Phosphodiesterase 4-targeted treatments for autoimmune diseases

    PubMed Central

    2013-01-01

    Advancements in phosphodiesterase (PDE)-targeted therapies have shown promise in recent years for treating patients with a variety of autoimmune diseases. This review summarizes the development of PDE4 inhibitors and the associated literature with a focus on treatments for autoimmune diseases. After the initial investigations of the prototypic PDE inhibitor, rolipram, more selective inhibitors targeting the PDE4 isozyme have been developed. With phase II and phase III clinical trials currently underway to evaluate the safety and efficacy of the latest generation of PDE4 inhibitors, namely apremilast, a new class of treatments may be around the corner for patients suffering from chronic, autoimmune diseases. PMID:23557064

  3. Perceptions of erectile dysfunction and phosphodiesterase type 5 inhibitor therapy in a qualitative study of men and women in affected relationships.

    PubMed

    McGraw, Sarah A; Rosen, Raymond C; Althof, Stanley E; Dunn, Marian; Cameron, Ann; Wong, David

    2015-01-01

    Erectile dysfunction negatively affects men and women in relationships; however, the subjective experience of erectile dysfunction and phosphodiesterase-type 5 inhibitor therapy remains poorly understood. The authors therefore characterized participants' subjective understanding of erectile dysfunction and phosphodiesterase-type 5 inhibitor therapy using individual interviews with affected heterosexual men (n = 58) and women (n = 65). Responses were characterized by 6 psychosocial domains: explanation of the experience, emotional responses, socially expected responses, value of sex, communication with the partner, and treatment expectations. The findings may aid clinicians in relating to men with erectile dysfunction and thus potentially improve effectiveness of therapy. PMID:24274107

  4. Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil

    SciTech Connect

    Wang, H.; Ye, M; Robinson, H; Fransis, S; Ke, H

    2007-01-01

    Vardenafil has higher affinity to phosphodiesterase-5 (PDE5) than sildenafil and lower administered dosage for the treatment of erectile dysfunction. However, the molecular basis for these differences is puzzling because two drugs have similar chemical structures. Reported here is a crystal structure of the fully active and nonmutated PDE5A1 catalytic domain in complex with vardenafil. The structure shows that the conformation of the H-loop in the PDE5A1-vardenafil complex is different from those of any known structures of the unliganded PDE5 and its complexes with the inhibitors. In addition, the molecular configuration of vardenafil differs from that of sildenafil when bound to PDE5. It is noteworthy that the binding of vardenafil causes loss of the divalent metal ions that have been observed in all the previously published PDE structures. The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs.

  5. Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Verdenafil and Sildenafil

    SciTech Connect

    Wang,H.; Ye, M.; Robinson, H.; Francis, S.; Ke, H.

    2008-01-01

    Vardenafil has higher affinity to phosphodiesterase-5 (PDE5) than sildenafil and lower administered dosage for the treatment of erectile dysfunction. However, the molecular basis for these differences is puzzling because two drugs have similar chemical structures. Reported here is a crystal structure of the fully active and nonmutated PDE5A1 catalytic domain in complex with vardenafil. The structure shows that the conformation of the H-loop in the PDE5A1-vardenafil complex is different from those of any known structures of the unliganded PDE5 and its complexes with the inhibitors. In addition, the molecular configuration of vardenafil differs from that of sildenafil when bound to PDE5. It is noteworthy that the binding of vardenafil causes loss of the divalent metal ions that have been observed in all the previously published PDE structures. The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs.

  6. Administration of the Phosphodiesterase Type 4 Inhibitor Rolipram into the Amygdala at a Specific Time Interval after Learning Increases Recognition Memory Persistence

    ERIC Educational Resources Information Center

    Werenicz, Aline; Christoff, Raissa R.; Blank, Martina; Jobim, Paulo F. C.; Pedroso, Thiago R.; Reolon, Gustavo K.; Schroder, Nadja; Roesler, Rafael

    2012-01-01

    Here we show that administration of the phosphodiesterase type 4 (PDE4) inhibitor rolipram into the basolateral complex of the amygdala (BLA) at a specific time interval after training enhances memory consolidation and induces memory persistence for novel object recognition (NOR) in rats. Intra-BLA infusion of rolipram immediately, 1.5 h, or 6 h…

  7. Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor.

    PubMed Central

    Genain, C P; Roberts, T; Davis, R L; Nguyen, M H; Uccelli, A; Faulds, D; Li, Y; Hedgpeth, J; Hauser, S L

    1995-01-01

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 PMID:7536938

  8. Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.

    PubMed

    Huang, Manna; Shao, Yongxian; Hou, Jianying; Cui, Wenjun; Liang, Beibei; Huang, Yingchun; Li, Zhe; Wu, Yinuo; Zhu, Xinhai; Liu, Peiqing; Wan, Yiqian; Ke, Hengming; Luo, Hai-Bin

    2015-11-01

    Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors. PMID:26316540

  9. The effect of phosphodiesterase inhibitors on the extinction of cocaine-induced conditioned place preference in mice.

    PubMed

    Liddie, Shervin; Anderson, Karen L; Paz, Andres; Itzhak, Yossef

    2012-10-01

    Several phosphodiesterase inhibitors (PDEis) improve cognition, suggesting that an increase in brain cAMP and cGMP facilitates learning and memory. Since extinction of drug-seeking behavior requires associative learning, consolidation and formation of new memory, the present study investigated the efficacy of three different PDEis in the extinction of cocaine-induced conditioned place preference (CPP) in B6129S mice. Mice were conditioned by escalating doses of cocaine which was resistant to extinction by free exploration. Immediately following each extinction session mice received (a) saline/vehicle, (b) rolipram (PDE4 inhibitor), (c) BAY-73-6691 (PDE9 inhibitor) or (d) papaverine (PDE10A inhibitor). Mice that received saline/vehicle during extinction training showed no reduction in CPP for >10 days. BAY-73-6691 (a) dose-dependently increased cGMP in hippocampus and amygdala, (b) significantly facilitated extinction and (c) diminished the reinstatement of cocaine CPP. Rolipram, which selectively increased brain cAMP levels, and papaverine which caused increases in both cAMP and cGMP levels, had no significant effect on the extinction of cocaine CPP. The results suggest that increase in hippocampal and amygdalar cGMP levels via blockade of PDE9 has a prominent role in the consolidation of extinction learning. PMID:22596207

  10. Title efficacy of phosphodiesterase 5 inhibitor on distant burn-induced muscle autophagy, microcirculation, and survival rate.

    PubMed

    Hosokawa, Sachiko; Koseki, Hiroaki; Nagashima, Michio; Maeyama, Yoshihiro; Yomogida, Kentaro; Mehr, Chelsea; Rutledge, Madeleine; Greenfeld, Hannah; Kaneki, Masao; Tompkins, Ronald G; Martyn, J A Jeevendra; Yasuhara, Shingo E

    2013-05-01

    Skeletal muscle wasting is an exacerbating factor in the prognosis of critically ill patients. Using a systemic burn injury model in mice, we have established a role of autophagy in the resulting muscle wasting that is distant from the burn trauma. We provide evidence that burn injury increases the autophagy turnover in the distal skeletal muscle by conventional postmortem tissue analyses and by a novel in vivo microscopic method using an autophagy reporter gene (tandem fluorescent LC3). The effect of tadalafil, a phosphodiesterase 5 inhibitor (PDE5I), on burn-induced skeletal muscle autophagy is documented and extends our published results that PDE5Is attenuates muscle degeneration in a muscular dystrophy model. We also designed a translational experiment to examine the impact of PDE5I on whole body and demonstrated that PDE5I administration lessened muscle atrophy, mitigated microcirculatory disturbance, and improved the survival rate after burn injury. PMID:23512808

  11. Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase-Knockout Mice.

    PubMed

    Forkuo, Gloria S; Kim, Hosu; Thanawala, Vaidehi J; Al-Sawalha, Nour; Valdez, Daniel; Joshi, Radhika; Parra, Sergio; Pera, Tonio; Gonnella, Patricia A; Knoll, Brian J; Walker, Julia K L; Penn, Raymond B; Bond, Richard A

    2016-08-01

    Mice lacking the endogenous β2-adrenoceptor (β2AR) agonist epinephrine (phenylethanolamine N-methyltransferase [PNMT]-knockout mice) are resistant to developing an "asthma-like" phenotype in an ovalbumin sensitization and challenge (Ova S/C) model, and chronic administration of β2AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various β2AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous β2AR agonists on allergic lung inflammation can be explained by qualitative β2AR signaling. The β2AR can signal through at least two pathways: the canonical Gαs-cAMP pathway and a β-arrestin-dependent pathway. Previous studies suggest that β-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of Gαs-cAMP signaling. This study was designed to test whether the in vitro antiinflammatory effects of phosphodiesterase 4 inhibitors, known to increase intracellular cAMP in multiple airway cell types, attenuate the asthma-like phenotype produced by the β2AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing β2AR signaling toward Gαs-cAMP pathway is beneficial. Airway inflammatory cells, epithelial mucus production, and airway hyperresponsiveness were quantified. In Ova S/C PNMT-KO mice, formoterol and salmeterol restored the asthma-like phenotype comparable to Ova S/C wild-type mice. However, coadministration of either roflumilast or rolipram attenuated this formoterol- or salmeterol-driven phenotype in Ova S/C PNMT-KO. These findings suggest that amplification of β2AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by β-agonists. PMID:26909542

  12. Impact on monoclonal antibody production in murine hybridoma cell cultures of adenosine receptor antagonists and phosphodiesterase inhibitors.

    PubMed

    Kelso, Geoffrey F; Kazi, Shahid A; Harris, Simon J; Boysen, Reinhard I; Chowdhury, Jamil; Hearn, Milton T W

    2016-01-15

    The effects of different adenosine receptor antagonists and cyclic nucleotide phosphodiesterase (PDE) inhibitors on monoclonal antibody (mAb) titer and cell viability of murine hybridoma cells in culture were measured as part of our investigations to discover additives that enhance mAb production. Specific adenosine receptor antagonists and PDE inhibitors were found to enhance or decrease the titer of immunoglobulin G1 (IgG1) mAbs relative to negative controls, depending on the specific compound and cell line employed. The observed enhancements or decreases in IgG1 mAb titer appeared to be mainly due to an increase or decrease in specific productivity rates (ngmAb/cell), respectively. The different effects of the selective adenosine antagonists suggest that antagonism at the level of the adenosine A2A and A1 or the adenosine A3 receptors result in either enhancement or suppression of IgG1 mAb production by hybridoma cells. Overall, these studies have identified hitherto unknown activities of specific adenosine antagonists and PDE inhibitors which indicate they may have valuable roles as cell culture additives in industrial biomanufacturing processes designed to enhance the yields of mAbs or other recombinant proteins produced by mammalian cell culture procedures. PMID:26646217

  13. A phosphodiesterase type-5 inhibitor, sildenafil, induces sperm capacitation and penetration into porcine oocytes in a chemically defined medium.

    PubMed

    Ioki, Sumire; Wu, Qing-Shan; Takayama, Osamu; Motohashi, Hideyuki H; Wakai, Takuya; Funahashi, Hiroaki

    2016-02-01

    The present study was undertaken to determine the effect of a phosphodiesterase (PDE) type-5 (cyclic guanosine monophosphate-specific) inhibitor, sildenafil, on capacitation and penetration of boar spermatozoa in a basic chemically defined medium (adenosine- and theophylline-free PGM-tac4). When ejaculated spermatozoa were cultured for 90 minutes in the absence or presence of sildenafil at 2.5 mM, the inhibitor significantly increased the percentage of capacitated/acrosome-reacted spermatozoa, as a result of the chlortetracycline assay. When fresh spermatozoa were co-cultured with oocytes in the presence of sildenafil at a different concentration (0, 2.5, 25, or 250 μM), higher sildenafil concentrations (25 and 250 μM) significantly resulted in higher sperm penetration rates. When oocytes matured in vitro were co-cultured with spermatozoa in the presence of 25 μM sildenafil or 25 mM caffeine benzoate for 8 hours, the incidence of penetrated oocytes did not differ between two groups, whereas the incidence of monospermic oocytes in penetrated one was significantly higher in the presence of sildenafil. Immunocytochemical analysis reported the presence of PDE type-5 on the acrosome region of boar spermatozoa. These results report that regulation of cyclic guanosine monophosphate-specific PDE type-5 by sildenafil somehow can increase the penetrability of boar spermatozoa in vitro. PMID:26443234

  14. Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

    PubMed Central

    Kiebala, Michelle; Maggirwar, Sanjay B.

    2011-01-01

    Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A2A receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND. PMID:21494611

  15. Surface plasmon resonance biosensor assay for the analysis of small-molecule inhibitor binding to human and parasitic phosphodiesterases.

    PubMed

    Siderius, Marco; Shanmugham, Anitha; England, Paul; van der Meer, Tiffany; Bebelman, Jan Paul; Blaazer, Antoni R; de Esch, Iwan J P; Leurs, Rob

    2016-06-15

    In the past decade, surface plasmon resonance (SPR) biosensor-based technology has been exploited more and more to characterize the interaction between drug targets and small-molecule modulators. Here, we report the successful application of SPR methodology for the analysis of small-molecule binding to two therapeutically relevant cAMP phosphodiesterases (PDEs), Trypanosoma brucei PDEB1 which is implicated in African sleeping sickness and human PDE4D which is implicated in a plethora of disease conditions including inflammatory pulmonary disorders such as asthma, chronic obstructive pulmonary disease and central nervous system (CNS) disorders. A protocol combining the use of directed capture using His-tagged PDE_CDs with covalent attachment to the SPR surface was developed. This methodology allows the determination of the binding kinetics of small-molecule PDE inhibitors and also allows testing their specificity for the two PDEs. The SPR-based assay could serve as a technology platform for the development of highly specific and high-affinity PDE inhibitors, accelerating drug discovery processes. PMID:27033007

  16. Phosphodiesterase type 5 inhibitors for treating erectile dysfunction and lower urinary tract symptoms secondary to benign prostatic hyperplasia: A comprehensive review.

    PubMed

    Haddad, Albert; Jabbour, Michel; Bulbul, Muhammad

    2015-09-01

    Many men have coexistent erectile dysfunction (ED) and lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Phosphodiesterase type 5 (PDE5) inhibitors are effective for treating both of these conditions independently. In this review we summarise the evidence supporting a link between ED and LUTS/BPH, and the results from key clinical studies related to the use of PDE5 inhibitors for treating both conditions. The results from these studies suggest that men who have both ED and LUTS/BPH, and are concerned about their sexual dysfunction, might benefit from single-agent, holistic treatment with a PDE5 inhibitor. PMID:26413339

  17. Phosphodiesterase type 5 inhibitors for treating erectile dysfunction and lower urinary tract symptoms secondary to benign prostatic hyperplasia: A comprehensive review

    PubMed Central

    Haddad, Albert; Jabbour, Michel; Bulbul, Muhammad

    2015-01-01

    Many men have coexistent erectile dysfunction (ED) and lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Phosphodiesterase type 5 (PDE5) inhibitors are effective for treating both of these conditions independently. In this review we summarise the evidence supporting a link between ED and LUTS/BPH, and the results from key clinical studies related to the use of PDE5 inhibitors for treating both conditions. The results from these studies suggest that men who have both ED and LUTS/BPH, and are concerned about their sexual dysfunction, might benefit from single-agent, holistic treatment with a PDE5 inhibitor. PMID:26413339

  18. Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2).

    PubMed

    Kankanala, Jayakanth; Marchand, Christophe; Abdelmalak, Monica; Aihara, Hideki; Pommier, Yves; Wang, Zhengqiang

    2016-03-24

    Tyrosyl DNA phosphodiesterase II (TDP2) is a recently discovered enzyme that specifically repairs DNA damages induced by topoisomerase II (Top2) poisons and causes resistance to these drugs. Inhibiting TDP2 is expected to enhance the efficacy of clinically important Top2-targeting anticancer drugs. However, TDP2 as a therapeutic target remains poorly understood. We report herein the discovery of isoquinoline-1,3-dione as a viable chemotype for selectively inhibiting TDP2. The initial hit compound 43 was identified by screening our in-house collection of synthetic compounds. Further structure-activity relationship (SAR) studies identified numerous analogues inhibiting TDP2 in low micromolar range without appreciable inhibition against the homologous TDP1 at the highest testing concentration (111 μM). The best compound 64 inhibited recombinant TDP2 with an IC50 of 1.9 μM. The discovery of this chemotype may provide a platform toward understanding TDP2 as a drug target. PMID:26910725

  19. Phosphodiesterase-2 inhibitor reverses corticosterone-induced neurotoxicity and related behavioural changes via cGMP/PKG dependent pathway.

    PubMed

    Xu, Ying; Pan, Jianchun; Chen, Ling; Zhang, Chong; Sun, Jiao; Li, Jianxin; Nguyen, Linda; Nair, Neetu; Zhang, Hanting; O'Donnell, James M

    2013-05-01

    Phosphodiesterase 2 (PDE2) is an enzyme responsible for hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to restrict intracellular signalling of these second messenger molecules. This study investigated how PDE2 inhibitor Bay 60-7550 affects the dysregulated glucocorticoid signalling in neuronal cells and regulates depressive behaviours after chronic stress in mice. We found that exposure of hippocampal neurons to corticosterone resulted in time- and concentration-dependent increases in PDE2 expression. These intriguing findings were confirmed in the hippocampal cell line HT-22. After corticosterone exposure for 24 h, HT-22 cells showed a concentration-dependent increase in mRNA levels for PDE2 subtypes, PDE2A1 and 2A3, as well as for the total PDE2A protein expression. Bay 60-7550 was found to reverse the cell lesion induced by corticosterone (50 μm). This neuroprotective effect was blocked by pretreatment with protein kinase G inhibitor KT5823, but not protein kinase A inhibitor H89, suggesting the involvement of cGMP-dependent signalling. Although Bay 60-7550 treatment for 24 h did not change the levels of phosphorylated mitogen-activated protein kinases ERK1/2 (pERK) and phosphorylated cAMP response element-binding protein (pCREB), it down-regulated pERK at 2 h and up-regulated a CREB co-activator, CREB-binding protein, at 24 h. Both of these effects were blocked by KT 5823. Furthermore, Bay 60-7550 reversed corticosterone-induced down-regulation of brain-derived neurotrophic factor protein levels 24 h after corticosterone exposure. In behavioural testing, Bay 60-7550 produced antidepressant-like effects and reduced corticosterone levels in stressed mice, further supporting the involvement of a PDE2-dependent pathway in mediating Bay 60-7550's effect during stress hormone insults. PMID:22850435

  20. Testosterone and phosphodiesterase type-5 inhibitors: new strategy for preventing endothelial damage in internal and sexual medicine?

    PubMed Central

    Aversa, Antonio; Bruzziches, Roberto; Francomano, Davide; Natali, Marco; Lenzi, Andrea

    2009-01-01

    Normal vascular endothelium is essential for the synthesis and release of substances affecting vascular tone (e.g. nitric oxide; NO), cell adhesion (e.g. endothelins, interleukins), and the homeostasis of clotting and fibrinolysis (e.g. plasminogen inhibitors, von Willebrand factor). The degeneration of endothelial integrity promotes adverse events (AEs) leading to increased atherogenesis and to the development of vascular systemic and penile end-organ disease. Testosterone (T) is an important player in the regulation of vascular tone through non-genomic actions exerted via blockade of extracellular-calcium entry or activation of potassium channels; also, adequate T concentrations are paramount for the regulation of phosphodiesterase type-5 (PDE5) expression and finally, for the actions exerted by hydrogen sulphide, a gas involved in the alternative pathway controlling vasodilator responses in penile tissue. It is known that an age-related decline of serum T is reported in approximately 20 to 30% of men whereas T deficiency is reported in up to 50% of men with metabolic syndrome or diabetes. A number of laboratory and human studies have shown the combination of T and other treatments for erectile dysfunction (ED), such as PDE5 inhibitors, to be more beneficial in patients with ED and hypogonadism, who fail monotherapy for sexual disturbances. The aim of this review is to show evidence on the role of T and PDE5 inhibitors, alone or in combination, as potential boosters of endothelial function in internal medicine diseases associated with reduced T or NO bioavailability, i.e. metabolic syndrome, obesity, diabetes, coronary artery disease, hyperhomocysteinemia, that share common risk factors with ED. Furthermore, the possibility of such a strategy to prevent endothelial dysfunction in men at increased cardiovascular risk is discussed. PMID:21789066

  1. Anti-inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus-inducible cytokines.

    PubMed

    Edwards, Michael R; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Johnston, Sebastian L

    2016-02-01

    Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS-2B), we investigated the potential anti-inflammatory effects of CHF6001 on rhinovirus (RV1B)-induced cytokines. Cytokine mRNA was measured by real-time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7-point dose-response curve (1000-0.001 nmol/L) as a 1.5-h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B-induced IL-8, IL-29, IP-10, and RANTES mRNA and protein in a concentration-dependent manner. Generally, CHF6001 was 13- to 16-fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL-8, IL-29, IP-10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV-induced cytokines when compared with steroid or CHF6001 alone. Combined low-dose steroid and low-dose CHF6001 had a similar efficacy as high-dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti-inflammatory activity against virus-induced inflammatory mediators and that CHF6001 is more potent than roflumilast. PMID:26977295

  2. The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse

    PubMed Central

    Beardsley, Patrick M.; Shelton, Keith L.; Hendrick, Elizabeth; Johnson, Kirk W.

    2010-01-01

    Stress and renewed contact with drug (a “slip”) have been linked to persisting relapse of methamphetamine abuse. Human brain microglial activation has been linked with methamphetamine abuse, and inhibitors of glial cell activation, certain phosphodiesterase (PDE) inhibitors, and glial cell derived neurotrophic factor (GDNF) have been reported to modulate drug abuse effects. Our objective was to determine whether the glial cell attenuator, 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine (AV411, ibudilast), a non-selective PDE inhibitor and promoter of GDNF, could reduce stress- and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior. Male Long-Evans hooded rats were trained to lever press reinforced with 0.1 mg/kg i.v. methamphetamine infusion according to fixed-ratio 1 (FR1) reinforcement schedules during daily, 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions and doses of 0 (vehicle), 2.5 and 7.5 mg/kg AV411 were then administered intraperitoneally b.i.d. on the last two days of extinction and then once on the testday to separate groups of 12 rats. During testing, the rats were given 15 min of intermittent footshock or a 1 mg/kg i.p. methamphetamine prime followed by a 2-h reinstatement test session. AV411 significantly reduced response levels of footshock-induced (2.5 and 7.5 mg/kg) and prime-induced (7.5 mg/kg) reinstatement of extinguished methamphetamine-maintained responding. AV411 has properties consistent with the ability to attenuate relapse precipitated by stress and methamphetamine “slips” during abstinence. These results thus reinforce interest in atypical neurobiological mechanisms which could be exploited for developing novel medications for treating drug abuse disorders. PMID:20399770

  3. [Application of precursor ion scanning method in rapid screening of illegally added phosphodiesterase-5 inhibitors and their unknown derivatives in Chinese traditional patent medicines and health foods].

    PubMed

    Sun, Jing; Cao, Ling; Feng, Youlong; Tan, Li

    2014-11-01

    The compounds with similar structure often have similar pharmacological activities. So it is a trend for illegal addition that new derivatives of effective drugs are synthesized to avoid the statutory test. This bring challenges to crack down on illegal addition behavior, however, modified derivatives usually have similar product ions, which allow for precursor ion scanning. In this work, precursor ion scanning mode of a triple quadrupole mass spectrometer was first applied to screen illegally added drugs in complex matrix such as Chinese traditional patent medicines and healthy foods. Phosphodiesterase-5 inhibitors were used as experimental examples. Through the analysis of the structure and mass spectrum characteristics of the compounds, phosphodiesterase-5 inhibitors were classified, and their common product ions were screened by full scan of product ions of typical compounds. Then high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method with precursor ion scanning mode was established based on the optimization of MS parameters. The effect of mass parameters and the choice of fragment ions were also studied. The method was applied to determine actual samples and further refined. The results demonstrated that this method can meet the need of rapid screening of unknown derivatives of phosphodiesterase-5 inhibitors in complex matrix, and prevent unknown derivatives undetected. This method shows advantages in sensitivity, specificity and efficiency, and is worth to be further investigated. PMID:25764652

  4. Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety.

    PubMed

    Beer, B; Chasin, M; Clody, D E; Vogel, J R

    1972-04-28

    Drugs that reduce anxiety may be mediated by cyclic adenosine monophosphate in the brain because (i) potent anxiety-reducing drugs are also potent inhibitors of brain phosphodiesterase activity; (ii) dibutyryl cyclic adenosine monophosphate has the ability to reduce anxiety; (iii) the methylxanthines show significant anxiety-reducing effects; (iv) theophylline and chlordiazepoxide produce additive anxiety-reducing activity; and (v) there is a significant correlation between the anxiety-reducing property of drugs and their ability to inhibit phosphodiesterase activity in the brain. PMID:4402069

  5. The long-acting phosphodiesterase inhibitor tadalafil does not influence athletes' VO2max, aerobic, and anaerobic thresholds in normoxia.

    PubMed

    Di Luigi, L; Baldari, C; Pigozzi, F; Emerenziani, G P; Gallotta, M C; Iellamo, F; Ciminelli, E; Sgrò, P; Romanelli, F; Lenzi, A; Guidetti, L

    2008-02-01

    Whereas experimental studies showed that in healthy trained subjects, the phosphodiesterase-5 inhibitor (PDE-5i) sildenafil improves exercise capacity in hypoxia and not in normoxia, no studies on the effects of the long half-life PDE-5i tadalafil exist. In order to evaluate whether tadalafil influences functional parameters and performance during a maximal exercise test in normoxia, we studied 14 healthy male athletes in a double-blind cross-over protocol. Each athlete performed two tests on a cycle ergometer, both after placebo or tadalafil (at therapeutic dose: 20 mg) administration. Oxygen consumption (VO2), blood lactate, respiratory exchange ratio, rate of perceived exertion, arterial blood pressure (BP), heart frequency (HR) and oxygen pulse (VO2/HR) were evaluated before exercise, at individual ventilatory and anaerobic thresholds (IVT and IAT), at VO2max and during recovery. Compared to placebo, a single tadalafil administration significantly reduced systolic BP before and after exercise (p < 0.05), decreased VO2/HR at IVT (13.3 +/- 1.8 vs. 14.5 +/- 2.1 mL . beat (-1); p = 0.03), but did not modify individual VO2max, IVT, or IAT. In healthy athletes, 20 mg of tadalafil does not substantially influence physical fitness-related parameters, exercise tolerance, and cardiopulmonary responses to maximal exercise in normoxia; it remains to be verified if higher doses/prolonged use influence health and/or sport performance in field conditions. PMID:17614028

  6. Phosphodiesterase Type 5 Inhibitor Sildenafil Decreases the Proinflammatory Chemokine CXCL10 in Human Cardiomyocytes and in Subjects with Diabetic Cardiomyopathy.

    PubMed

    Di Luigi, Luigi; Corinaldesi, Clarissa; Colletti, Marta; Scolletta, Sabino; Antinozzi, Cristina; Vannelli, Gabriella B; Giannetta, Elisa; Gianfrilli, Daniele; Isidori, Andrea M; Migliaccio, Silvia; Poerio, Noemi; Fraziano, Maurizio; Lenzi, Andrea; Crescioli, Clara

    2016-06-01

    T helper 1 (Th1) type cytokines and chemokines are bioactive mediators in inflammation underling several diseases and co-morbid conditions, such as cardiovascular and metabolic disorders. Th1 chemokine CXCL10 participates in heart damage initiation/progression; cardioprotection has been recently associated with sildenafil, a type 5 phosphodiesterase inhibitor. We aimed to evaluate the effect of sildenafil on CXCL10 in inflammatory conditions associated with diabetic cardiomyopathy. We analyzed: CXCL10 gene and protein in human cardiac, endothelial, and immune cells challenged by pro-inflammatory stimuli with and without sildenafil; serum CXCL10 in diabetic subjects at cardiomyopathy onset, before and after 3 months of treatment with sildenafil vs. placebo. Sildenafil significantly decreased CXCL10 protein secretion (IC50 = 2.6 × 10(-7)) and gene expression in human cardiomyocytes and significantly decreased circulating CXCL10 in subjects with chemokine basal level ≥ 930 pg/ml, the cut-off value as assessed by ROC analysis. In conclusion, sildenafil could be a pharmacologic tool to control CXCL10-associated inflammation in diabetic cardiomyopathy. PMID:27165639

  7. Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia

    PubMed Central

    Shih, Chung-Hung; Lin, Ling-Hung; Hsu, Hsin-Te; Wang, Kuo-Hsien; Lai, Chi-Yin; Chen, Chien-Ming; Ko, Wun-Chang

    2012-01-01

    Hesperetin, a selective phosphodiesterase (PDE)4 inhibitor, is present in the traditional Chinese medicine, “Chen Pi.” Therefore, we were interested in investigating its effects on ovalbumin- (OVA-) induced airway hyperresponsiveness, and clarifying its rationale for ameliorating asthma and chronic obstructive pulmonary disease (COPD). Hesperetin was revealed to have a therapeutic (PDE4H/PDE4L) ratio of >11. Hesperetin (10 ~ 30 μmol/kg, intraperitoneally (i.p.)) dose-dependently and significantly attenuated the airway hyperresponsiveness induced by methacholine. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF). It dose-dependently and significantly suppressed total and OVA-specific immunoglobulin E levels in the BALF and serum. However, hesperetin did not influence xylazine/ketamine-induced anesthesia, suggesting that hesperetin has few or no emetic effects. In conclusion, the rationales for ameliorating allergic asthma and COPD by hesperetin are anti-inflammation, immunoregulation, and bronchodilation. PMID:22454667

  8. The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia.

    PubMed

    Turner, Mark J; Matthes, Elizabeth; Billet, Arnaud; Ferguson, Amy J; Thomas, David Y; Randell, Scott H; Ostrowski, Lawrence E; Abbott-Banner, Kathy; Hanrahan, John W

    2016-01-01

    Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF. PMID:26545902

  9. Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches.

    PubMed

    Li, Jing; Zhou, Nan; Liu, Wen; Li, Jianzong; Feng, Yu; Wang, Xiaoyun; Wu, Chuanfang; Bao, Jinku

    2016-05-01

    cAMP, intracellular cyclic adenosine monophosphate, is a ubiquitous second messenger that plays a key role in many physiological processes. PDE4B which can reduce the cAMP level by hydrolyzing cAMP to 5'-AMP has become a therapeutic target for the treatment of human diseases such as respiratory disorders, inflammation diseases, neurological and psychiatric disorders. However, the use of currently available PDE4B inhibitors is restricted due to serious side effects caused by targeting PDE4D. Hence, we are attempting to find out subfamily-selective PDE4B inhibitors from natural products, using computer-aided approaches such as virtual screening, docking, and molecular dynamics simulation. Finally, four potential PDE4B-selective inhibitors (ZINC67912770, ZINC67912780, ZINC72320169, and ZINC28882432) were found. Compared to the reference drug (roflumilast), they scored better during the virtual screening process. Binding free energy for them was -317.51, -239.44, -215.52, and -165.77 kJ/mol, better than -129.05 kJ/mol of roflumilast. The pharmacophore model of the four candidate inhibitors comprised six features, including one hydrogen bond donor, four hydrogen bond acceptors, and one aromatic ring feature. It is expected that our study will pave the way for the design of potent PDE4B-selective inhibitors of new drugs to treat a wide variety of diseases such as asthma, COPD, psoriasis, depression, etc. PMID:26159554

  10. Phosphodiesterase 5A inhibitors improve functional recovery after stroke in rats: optimized dosing regimen with implications for mechanism.

    PubMed

    Menniti, Frank S; Ren, JingMei; Coskran, Timothy M; Liu, Jing; Morton, Daniel; Sietsma, Dana K; Som, Angel; Stephenson, Diane T; Tate, Barbara A; Finklestein, Seth P

    2009-12-01

    Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery after middle cerebral artery occlusion (MCA-o) in rats. We used the PDE5A inhibitor 3-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one hydrochloride (PF-5) to determine the timing, duration, and degree of inhibition that yields maximum efficacy. We also investigated the localization of PDE5A to determine the tissues and cells that would be targets for PDE5 inhibition and that may mediate efficacy. Nearly complete inhibition of PDE5A, starting 24 h after MCA-o and continued for 7 days, resulted in nearly complete recovery of sensorimotor function that was sustained for 3 months. Delaying administration until 72 h after MCA-o resulted in equivalent efficacy, whereas delaying treatment for 14 days was ineffective. Treatment for 7 days was equivalently efficacious to 28 or 84 days of treatment, whereas treatment for 1 day was less effective. In the normal forebrain, PDE5A immunoreactivity was prominent in smooth muscle of meningeal arteries and a few smaller blood vessels, with weak staining in a few widely scattered cortical neurons and glia. At 24 and 48 h after MCA-o, the number and intensity of blood vessel staining increased in the infarcted cortex and striatum. PDE5A immunoreactivity also was increased at 48 h in putative microglia in penumbra, whereas there was no change in staining of the scattered cortical neurons. Given the window for efficacy and the PDE5A distribution, we hypothesize that efficacy results from an effect on vasculature, and perhaps modulation of microglial function, both of which may facilitate recovery of neuronal function. PMID:19729580

  11. Salvage therapy trial for erectile dysfunction using phosphodiesterase type 5 inhibitors and vitamin E: preliminary report.

    PubMed

    Kondoh, Nobuyuki; Higuchi, Yoshihide; Maruyama, Takuo; Nojima, Michio; Yamamoto, Shingo; Shima, Hiroki

    2008-12-01

    We report our initial experience with salvage therapy for low responders to PDE-5 inhibitors by adding vitamin E. Of 89 patients with ED who visited our clinic between January 2004 to August 2006, 9 were unable to obtain a full response to a PDE-5 inhibitor and included in the present study. After providing informed consent, each was given 300 mg per day of alpha-tocophenol at least 1 month and completed IIEF-5 questionnaires to assess its efficacy while also taking a PDE-5 inhibitor. With alpha-tocophenol administration, the average IIEF-5 score increased from 13.8 +/- 3.2 to 17.1 +/- 3.6. Four of seven patients who completed the questionnaire each time showed improved IIEF-5 scores, with a maximum elevation of 9 points. Further, eight of the nine patients experienced favourable subjective changes, the majority being increased penile rigidity. The present clinical trial results are, to our knowledge, the first known to show the effects of vitamin E for enhancing the efficacy of a PDE-5 inhibitor. PMID:19172547

  12. Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors.

    PubMed

    Oliveira, Fernanda G; Sant'Anna, Carlos M R; Caffarena, Ernesto R; Dardenne, Laurent E; Barreiro, Eliezer J

    2006-09-01

    In the present work, several computational methodologies were combined to develop a model for the prediction of PDE4B inhibitors' activity. The adequacy of applying the ligand docking approach, keeping the enzyme rigid, to the study of a series of PDE4 inhibitors was confirmed by a previous molecular dynamics analysis of the complete enzyme. An exhaustive docking procedure was performed to identify the most probable binding modes of the ligands to the enzyme, including the active site metal ions and the surrounding structural water molecules. The enzyme-inhibitor interaction enthalpies, refined by using the semiempirical molecular orbital approach, were combined with calculated solvation free energies and entropy considerations in an empirical free energy model that enabled the calculation of binding free energies that correlated very well with experimentally derived binding free energies. Our results indicate that both the inclusion of the structural water molecules close to the ions in the binding site and the use of a free energy model with a quadratic dependency on the ligand free energy of solvation are important aspects to be considered for molecular docking investigations involving the PDE4 enzyme family. PMID:16843671

  13. Synthesis, Structural Analysis, and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors

    PubMed Central

    Castaño, Tania; Wang, Huanchen; Campillo, Nuria E.; Ballester, Sara; González-García, Coral; Hernández, Javier; Pérez, Concepción; Cuenca, Jimena; Pérez-Castillo, Ana; Martínez, Ana; Huertas, Oscar; Gelpí, José Luis; Luque, F. Javier; Ke, Hengming; Gil, Carmen

    2010-01-01

    PDE7 inhibitors regulate pro-inflammatory and immune T-cell functions, and are a potentially novel class of drugs especially useful in the treatment of a wide variety of immune and inflammatory disorders. Starting from our lead family of thioxoquinazolines, we designed, synthesized, and characterized a novel series of thioxoquinazoline derivatives. Many of these compounds showed inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7A1 and at the micromolar level against PDE4D2. Cell-based studies showed that these compounds not only increased intracellular cAMP levels, but also had interesting anti-inflammatory properties within a therapeutic window. The in silico data predict that these compounds are capable of the crossing the blood–brain barrier. The X-ray crystal structure of the PDE7A1 catalytic domain in complex with compound 15 at a resolution of 2.4 Å demonstrated that hydrophobic interactions at the active site pocket are a key feature. This structure, together with molecular modeling, provides insight into the selectivity of the PDE inhibitors and a template for the discovery of new PDE7 or PDE7/PDE4 dual inhibitors. PMID:19350606

  14. Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition.

    PubMed

    Jones, Philip G; Hewitt, Michael C; Campbell, John E; Quinton, Maria S; Engel, Sharon; Lew, Robert; Campbell, Una; Burdi, Douglas F

    2015-08-01

    In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. Using microdialysis, we show that 3mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3mg/kg (p.o.) corresponding to 59-86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications. PMID:25989044

  15. A Selective Phosphodiesterase-4 Inhibitor Reduces Leukocyte Infiltration, Oxidative Processes, and Tissue Damage after Spinal Cord Injury

    PubMed Central

    Fleming, Jennifer C.; Golshani, Roozbeh; Pearse, Damien D.; Kasabov, Levent; Brown, Arthur; Weaver, Lynne C.

    2011-01-01

    Abstract We tested the hypothesis that a selective phosphodiesterase type 4 inhibitor (PDE4-I; IC486051) would attenuate early inflammatory and oxidative processes following spinal cord injury (SCI) when delivered during the first 3 days after injury. Rats receiving a moderately severe thoracic-clip-compression SCI were treated with the PDE4-I (0.5, 1.0, and 3.0 mg/kg IV) in bolus doses from 2–60 h post-injury. Doses at 0.5 mg/kg and 1.0 mg/kg significantly decreased myeloperoxidase (MPO) enzymatic activity (neutrophils), expression of a neutrophil-associated protein and of ED-1 (macrophages), and estimates of lipid peroxidation in cord lesion homogenates at 24 h and 72 h post-injury by 25–40%. The 3.0 mg/kg dose had small or no effects on these measures. The PDE4-I treatment (0.5 or 1.0 mg/kg) reduced expression of the oxidative enzymes gp91phox, inducible nitric oxide synthase, and cyclooxygenase-2, and diminished free radical generation by up to 40%. Treatment with 0.5 mg/kg PDE4-I improved motor function (as assessed by the Basso-Beattie-Bresnahan scale) significantly from 4–8 weeks after SCI (average difference 1.3 points). Mechanical allodynia elicited from the hindpaw decreased by up to 25%. The PDE4-I treatment also increased white matter volume near the lesion at 8 weeks after SCI. In conclusion, the PDE4-I reduced key markers of oxidative stress and leukocyte infiltration, producing cellular protection, locomotor improvements, and a reduction in neuropathic pain. Early inhibition of PDE4 is neuroprotective after SCI when given acutely and briefly at sufficient doses. PMID:21355819

  16. A comparison of the available phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction: a focus on avanafil

    PubMed Central

    Evans, Jeffery D; Hill, Stephen R

    2015-01-01

    Background Numerous pathways can lead to erectile dysfunction (ED) in patients, with some patients having multiple causes. Regardless of the etiology, ED has been successfully treated in many patients with the advent of oral phosphodiesterase-5 inhibitors (PDE5Is). With the release of avanafil, there are currently four PDE5I options available, and choosing between them should be based on patient-specific considerations and preferences. Objective To review the treatment of ED with PDE5Is, taking into account the effectiveness, safety, and patient satisfaction of these agents, as well as avanafil’s place in therapy. Methods A PubMed search was completed to find articles published in English studying patient satisfaction and adherence to ED medication. Additional searches looked specifically for any data regarding the use of avanafil. Results ED is effectively treated in most patients with PDE5Is, with the most common side effects from the medications being headache, flushing, and visual disturbances. Patients have identified many different factors, such as efficacy, side effects, duration of action, and daily use, in determining overall satisfaction and the right medication for them. While avanafil does not have any patient satisfaction trials to date, it has been proven to be a safe and effective treatment for ED with possibly the fastest onset of action and fewer visual disturbances than its competitors. Conclusion Avanafil along with the other PDE5Is has shown to be a safe and effective oral treatment for ED, with avanafil’s possible place in therapy for patients who want an on-demand option or as an alternative in patients who experience visual disturbances with the other agents. PMID:26316720

  17. The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models.

    PubMed

    Shiraishi, Eri; Suzuki, Kazunori; Harada, Akina; Suzuki, Noriko; Kimura, Haruhide

    2016-03-01

    Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-d-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia. PMID:26675680

  18. Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax)

    PubMed Central

    Sánchez, Elisa; Rubio, Vera Cruz; Thompson, Darren; Metz, Juriaan; Flik, Gert; Millhauser, Glenn L.; Cerdá-Reverter, José Miguel

    2009-01-01

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor mainly expressed in the central nervous system of vertebrates. Activation of the MC4R leads to a decrease in food intake, whereas inactivating mutations are a genetic cause of obesity. The binding of agouti-related protein (AGRP) reduces not only agonist-stimulated cAMP production (competitive antagonist) but also the basal activity of the receptor, as an inverse agonist. Transgenic zebrafish overexpressing AGRP display increased food intake and linear growth, indicative of a physiological role for the melanocortin system in the control of the energy balance in fish. We report on the cloning, pharmacological characterization, tissue distribution, and detailed brain mapping of a sea bass (Dicentrarchus labrax) MC4R ortholog. Sea bass MC4R is profusely expressed within food intake-controlling pathways of the fish brain. However, the activity of the melanocortin system during progressive fasting does not depend on the hypothalamic/pituitary proopiomelanocortin (POMC) and MC4R expression, which suggests that sea bass MC4R is constitutively activated and regulated by AGRP binding. We demonstrate that AGRP acts as competitive antagonist and reduces MTII-induced cAMP production. AGRP also decreases the basal activity of the receptor as an inverse agonist. This observation suggests that MC4R is constitutively active and supports the evolutionary conservation of the AGRP/MC4R interactions. The inverse agonism, but not the competitive antagonism, depends on the presence of a phosphodiesterase inhibitor (IBMX). This suggests that inverse agonism and competitive antagonism operate through different intracellular signaling pathways, a view that opens up new targets for the treatment of melanocortin-induced metabolic syndrome. PMID:19225141

  19. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

    PubMed Central

    Kavanaugh, Arthur; Mease, Philip J; Gomez-Reino, Juan J; Adebajo, Adewale O; Wollenhaupt, Jürgen; Gladman, Dafna D; Lespessailles, Eric; Hall, Stephen; Hochfeld, Marla; Hu, ChiaChi; Hough, Douglas; Stevens, Randall M; Schett, Georg

    2014-01-01

    Objectives Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Conclusions Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT

  20. Are phosphodiesterase type 5 inhibitors effective for the management of lower urinary symptoms suggestive of benign prostatic hyperplasia?

    PubMed Central

    Zhang, Li Tao; Park, Jong Kwan

    2015-01-01

    AIM: To review the efficacy of phosphodiesterase type 5 inhibitors (PDE5-Is) in lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia (LUTS/BPH). METHODS: A comprehensive research was conducted to identify all publications relating to benign prostate hyperplasia and treatment with sildenafil, vardenafil and tadalafil. To assess the efficacy, the changes in total international prostate symptom score (IPSS), IPSS subscore including voiding, storage and quality of life (QoL), Benign prostatic hyperplasia Impact Index (BII), maximum urinary flow rate (Qmax) and the International Index of Erectile Function (IIEF) were extracted. A meta-analytical technique was used for the analysis of integrated data from the included studies to evaluate the mean difference in the results. RESULTS: Total IPSS score, IIEF and BII showed a significant improvement in trials in which LUTS/BPH with or without erectile dysfunction (ED) were compared with the placebo. For LUTS/BPH, the mean differences of total IPSS score, IIEF and BII are -2.17, 4.88 and -0.43, P < 0.00001, respectively. For LUTS/BPH with comorbid ED, the mean difference are -1.97, 4.54 and -0.52, P < 0.00001, respectively. PDE5-Is appear to improve IPSS storage, voiding and QoL subscore (mean difference = -0.71, -1.23 and -0.33, P < 0.00001, respectively). Although four doses of tadalafil (2.5, 5, 10 and 20 mg) failed to reach significance in Qmax (mean difference = 0.22, P = 0.10), the 5 mg dose of tadalafil significantly improved the Qmax (mean difference = 0.33, P = 0.03). CONCLUSION: PED5-Is demonstrated efficacy for improving LUTS in BPH patients with or without ED and could be considered to be the first line treatment for LUTS/BPH. PMID:25664256

  1. The Prescribing and Dispensing of Phosphodiesterase Type 5 Inhibitors in South Korea: A Questionnaire Survey of Patient Discomfort

    PubMed Central

    Kim, Sang Woo; Kim, Jong Wook; Chae, Ji Yun; Kim, Jin Wook; Yoon, Cheol Yong; Oh, Mi Mi; Park, Hong Seok; Kim, Je Jong

    2014-01-01

    Purpose This study was performed to investigate the discomfort reported by patients taking phosphodiesterase type 5 inhibitors (PDE5Is) in clinical practice. Materials and Methods From September 2011 to March 2012, we surveyed patients who were prescribed PDE5Is for erectile dysfunction (ED). The questionnaire elicited information concerning: patient characteristics, medication counseling received and inconveniences experienced in hospitals and at pharmacies, effects of PDE5Is, and the separation of the prescribing and the dispensing of PDE5Is. Results A total of 237 patients completed the questionnaire (mean age: 58.81±9.14 years). Among the 62 patients (26.0%) who reported having encountered some inconveniences in hospitals, the most frequently expressed concerns 'assistant staff,' including nurses (38.7%), 'testing procedures' (27.4%), and 'the issuing of prescriptions' (22.6%). Of the 137 patients (57.8%) who noted inconveniences in obtaining medications from pharmacies, 60.6% cited 'self-consciousness' as the most common reason, followed by 'insufficient medication counseling' (22.6%), and 'absence of consultation' (11.6%). In contrast, 82% of the patients were satisfied with the medication counseling that they had received in hospitals, covering drug usage, side effects, and precautions regarding PDE5Is; this proportion was only 30% for pharmacies. Further, most patients (89%) indicated that they preferred to obtain their prescriptions and medications for ED from the hospital at the same time. Conclusions Treatment of ED is a highly private matter. According to the survey, ED patients more often felt that obtaining medication from pharmacies was inconvenient. The sociocultural aspects of ED necessitate that exceptions to separating the prescribing and the dispensing of medication be considered. PMID:25237655

  2. Let's rethinking about the safety of phosphodiesterase type 5 inhibitor in the patients with erectile dysfunction after radical prostatectomy.

    PubMed

    Kim, Su Jin; Kim, Ju Ho; Chang, Hyun-Kyung; Kim, Khae Hawn

    2016-06-01

    As the radical prostatectomy (RP) for the patient diagnosed as localized prostate cancer has been increasing, erectile dysfunction (ED) associated with RP is increased and ED after RP is a significant risk factor to reduce the quality of life for the patient after RP. Therefore, the treatment concept called penile rehabilitation was introduced and phosphodiesterase type 5 inhibitor (PDE5I) is used widely for the prostate cancer patient after RP. Generally PDE5I is considered as safe and effective drug for the prostate cancer patient after RP. Recently, a report against the general opinion that PDE5I use is safe in the patient with prostate cancer was reported and the analysis of 5-yr biochemical recurrence-free survival after RP between the PDE5I users and non-PDE5I users after bilateral nerve sparing RP showed decreased 5-yr biochemical recurrence-free survival in the PDE5I users. In addition, a longitudinal cohort study reported that sildenafil, a kind of PDE5I, use might be associated with the development of melanoma and this result suggested the possibility of adverse effect of PDE5I on some kinds of cancers as well as prostate cancer. Moreover, the studies to evaluate the influence of nitric oxide (NO) and guanosine monophosphate (cGMP) signaling pathway associated with PDE5 showed both cancer reduction and cancer development. Therefore, the role of NO and cGMP signaling pathway in cancer was reviewed based on the previous studies and suggested the necessity of further clinical studies concerning about the safety of PDE5I in prostate cancer. PMID:27419107

  3. Determination of phosphodiesterase type V inhibitors in wastewater by direct injection followed by liquid chromatography coupled to tandem mass spectrometry.

    PubMed

    Causanilles, Ana; Emke, Erik; de Voogt, Pim

    2016-09-15

    A simple, fast and reliable analytical method for the determination of phosphodiesterase type V inhibitors in wastewater was developed and validated. The method was based on direct injection followed by liquid chromatography coupled to tandem mass spectrometry with triple quadrupole as mass analyzer. Transformation products and analogues were included in the target list besides the three active pharmaceutical ingredients (sildenafil, vardenafil and tadalafil). The method performance was thoroughly investigated, including the analyte stability in wastewater and matrix effect. All target compounds presented linear fits between their LOD and 500ng/L. The quantification limits ranged from 1.6 to 30ng/L for all compounds except for n-octylnortadalafil (LOQ: 100ng/L); precision calculated as intraday repeatability was lower than 30%; accuracy calculated as procedural recovery ranged successfully between 85 and 105% in all cases. The method was applied to samples collected during three week-long monitoring campaigns performed in 2013, 2014 and 2015 in three Dutch cities. Only sildenafil and its two metabolites, desmethyl- and desethylsildenafil, were present with normalized loads ranging from LOQ to 8.3, 11.8 and 21.6mg/day/1000 inh, respectively. Two additional week-long sets of samples were collected in Amsterdam at the time that a festival event took place, bringing around 350,000 visitors to the city. The difference in drug usage patterns was statistically studied: "weekday" versus "weekend", "normal" versus "atypical" week; and results discussed. The metabolite to parent drug concentration ratio evolution during consecutive years was discussed, leading to several possible explanations that should be further investigated. Finally, wastewater-based epidemiology approach was applied to back-calculate sildenafil consumption. PMID:27161135

  4. The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5.

    PubMed

    Wallis, R M

    1999-10-01

    Sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl) phenylsulphonyl]-4-methylpiperazine) has been shown to be an effective oral treatment for male erectile dysfunction. Sildenafil is a potent competitive inhibitor of PDE5 (IC50 3.5 nM) and is selective over PDE1 to 4 (80 to 19,000-fold) and retinal PDE6 (10-fold). Sildenafil enhanced cGMP accumulation driven with sodium nitroprusside in the corpus cavernosum of rabbits without affecting cAMP formulation. In the absence of nitric oxide drive, sildenafil had no functional effect on the human and rabbit isolated corpus cavernosum, but potently potentiated the relaxant effects of nitric oxide on these tissues. In the anaesthetised dog, sildenafil (ED50: 12 to 16 micrograms/kg i.v.) enhanced the increase in intracavernosal pressure induced by electrical stimulation of the pelvic nerve or intracavernosal injection of sodium nitroprusside in the absence of meaningful effects on blood pressure. Consistent with its mode of action, sildenafil potentiated the vasorelaxant effects of glyceryl trinitrate on rabbit isolated aortic rings. However, unlike milrinone, sildenafil had no inotropic effects on the dog isolated trabeculae carneae. Thus it is unlikely to have the deleterious effects on cardiac function associated with PDE3 inhibitors. As a consequence of inhibition of PDE6 in the retina, sildenafil (1 to 100 microM) altered the kinetics of the light response of the dog isolated retina. In the anaesthetised dog, sildenafil modified the a- and b-wave of the electroretinogram induced by a flash of blue light. These effects were proportional to plasma concentrations, were fully reversible and only occurred following plasma concentrations higher (approximately 30-fold) than those active on intracavernosal pressure. These studies have shown that sildenafil is a potent and selective inhibitor of PDE5. It enhances the effect of nitric oxide on the corpus cavernosum and has been shown

  5. Age-related changes of cyclic AMP phosphodiesterase activity in rat brain regions and a new phosphodiesterase inhibitor--nootropic agent adafenoxate.

    PubMed

    Stancheva, S L; Alova, L G

    1991-01-01

    1. The low- and high-KM cyclic AMP phosphodiesterase (cAMP PDE) activity in cerebral cortex, striatum, hypothalamus and hippocampus of young (4-5-month-old) and aged (22-month-old) rats has been studied. 2. A significant rise in the high-KM cAMP PDE activity in the cerebral cortex, hypothalamus and hippocampus in aged rats has been found. 3. The activity of the low-KM cAMP PDE does not change during senescence in all the brain structures studied. 4. In a series of increased concentrations (from 5 x 10(-4) to 1 x 10(-5) M) adafenoxate inhibits low- and high-KM cAMP PDE in most of the brain structures studied in both age groups. 5. The present results provide evidence for realization of the CNS effects of adafenoxate through inhibition of cAMP PDE activity and regulation of the intracellular level of cAMP. PMID:1662175

  6. In vitro and in vivo metabolism of CHF 6001, a selective phosphodiesterase (PDE4) inhibitor.

    PubMed

    Cenacchi, Valentina; Battaglia, Rosangela; Cinato, Flavio; Riccardi, Benedetta; Spinabelli, Daniele; Brogin, Giandomenico; Puccini, Paola; Pezzetta, Daniele

    2015-01-01

    1. The metabolism of CHF 6001, a novel PDE4 inhibitor, was determined in vitro in mouse, rat, dog, monkey and human microsomes and hepatocytes and in vivo in plasma, urine, feces and bile of rats after intravenous and intratracheal administration. 2. The behavior of CHF 6001 in microsomes and hepatocytes changed across species. CYP3A4/5 isoenzymes were identified to be the primary enzymes responsible for the metabolism of CHF 6001 in human liver microsomes. 3. In the rat, CHF 6001 was found extensively metabolized in urine, feces and bile, but not in plasma, where CHF 6001 was the main compound present. The metabolite profiles were different in the four biological matrices from both qualitative and quantitative point of view. 4. CHF 6001 was metabolized through hydrolysis with the formation of the alcohol CHF 5956, loss of a chlorine atom, loss of the N-oxide, hydroxylation, loss of the cyclopropylmethyl group in the alcohol moiety, conjugation with glucuronic acid, glutathione and cysteine-glycine. 5. The major metabolite present in the bile was isolated and characterized by nuclear magnetic resonance analysis. It derived from CHF 6001 through contraction of the pyridine-N-oxide ring to N-hydroxy pyrrole and conjugation with glucuronic acid. PMID:25733029

  7. Is there a role for phosphodiesterase type-5 inhibitors in the treatment of premature ejaculation?

    PubMed

    Aversa, A; Francomano, D; Bruzziches, R; Natali, M; Spera, G; Lenzi, A

    2011-01-01

    Premature ejaculation (PE) is considered to be the most common male sexual dysfunction. The realization that PE may co-exist with ED prompted the use of PDE5-i's alone or in combination with selective serotonin reuptake inhibitors (SSRIs) for treating ejaculatory disorders. Until recently, there was little evidence that PDE5-i's alone may have a role in the treatment of PE in the absence of ED, and current available treatments include only on-demand dapoxetine. However, available data indicate that there is clinical, anatomical, physiological, pharmacological and genetic evidence to explain the efficacy of PDE5-i's. Nine manuscripts that examined the efficacy of PDE5-i's in the treatment of PE, alone or in combination with SSRIs, were retrieved. All studies reported some significant changes in the intravaginal ejaculatory latency time and sexual satisfaction scores, although not all were clinically meaningful. Well-designed multicenter studies are urgently required to further elucidate the efficacy and safety, as well as the mechanisms of action of PDE5-i's in the treatment of PE. The aim of this review is to discuss basic rationale and to show clinical evidence sustaining the possibility to use off-label PDE5-i's to treat PE. PMID:21270821

  8. Stimulation of the hypothalamo-pituitary-adrenal axis in the rat by the type 4 phosphodiesterase (PDE-4) inhibitor, denbufylline.

    PubMed Central

    Hadley, A. J.; Kumari, M.; Cover, P. O.; Osborne, J.; Poyser, R.; Flack, J. D.; Buckingham, J. C.

    1996-01-01

    1. Preliminary studies in our laboratories showed that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally to adult male rats. This paper describes the results of experiments in which well established in vivo and in vitro models were used to (a) examine further the effects of denbufylline on HPA function and (b) identify the site and mode of action of the drug within the axis. 2. In vivo, administration of denbufylline (0.1-2.5 mg kg-1, i.p.) produced a significant increase in the serum corticosterone concentration; maximal responses were attained at a dose of 1.0 mg kg-1 (P < 0.01 vs. vehicle control, Scheffe's test). However, when denbufylline was administered by intracerebroventricular injection (0.05-1 micrograms kg-1) it failed to influence significantly the serum corticosterone concentration (P > 0.05 vs. vehicle control, Scheffe's test). The adrenocortical responses to peripheral injections of denbufylline (1 mg kg-1, i.p.) were reduced in rats in which the secretion of endogenous corticotrophin releasing factors (CRFs) from the hypothalamus was blocked pharmacologically (P < 0.01 vs. controls, Scheffe's test). However, denbufylline (0.1 mg kg-1, i.p.) potentiated the significant (P < 0.01) increases in serum corticosterone concentration provoked in "CRF blocked rats' by hypothalamic extract (5 hypothalamic extracts kg-1, i.v.) although it failed to influence (P > 0.05) the relatively moderate increases in corticosterone secretion evoked by CRH-41 (2 mg kg-1, i.v.). 3. In vitro, denbufylline (0.01-1 mM) evoked small but significant (P < 0.05) increases in the release of ACTH from rat anterior pituitary segments; furthermore, at these and lower concentrations (0.01 microM-1 mM), it potentiated the adrenocorticotrophic responses to sub-maximal concentrations of hypothalamic extract (P < 0.01) and forskolin (0.1 mM, P < 0

  9. 8-(3-chloro-4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors.

    PubMed

    Sakamoto, Toshiaki; Koga, Yuichi; Hikota, Masataka; Matsuki, Kenji; Mochida, Hideki; Kikkawa, Kohei; Fujishige, Kotomi; Kotera, Jun; Omori, Kenji; Morimoto, Hiroshi; Yamada, Koichiro

    2015-04-01

    A novel series of highly selective phosphodiesterase 5 (PDE5) inhibitors was found. 8H-Pyrido[2,3-d]pyrimidin-7-one derivatives bearing an (S)-2-(hydroxymethyl)pyrrolidin-1-yl group at the 2-position and a 3-chloro-4-methoxybenzyl group at the 8-position exhibited potent PDE5 inhibitory activities and high PDE5 selectivity over PDE6. Among the synthesized compounds, the 5-methyl analogue (5b) showed the most potent relaxant effect on isolated rabbit corpus cavernosum with an EC30 value of 0.85 nM. PMID:25754491

  10. Discovery of [¹¹C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors.

    PubMed

    Cox, Christopher D; Hostetler, Eric D; Flores, Broc A; Evelhoch, Jeffrey L; Fan, Hong; Gantert, Liza; Holahan, Marie; Eng, Waisi; Joshi, Aniket; McGaughey, Georgia; Meng, Xiangjun; Purcell, Mona; Raheem, Izzat T; Riffel, Kerry; Yan, Youwei; Renger, John J; Smith, Sean M; Coleman, Paul J

    2015-11-01

    Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [(11)C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey. PMID:26077491

  11. Phosphodiesterase inhibitors as a new generation of antiprotozoan drugs: exploiting the benefit of enzymes that are highly conserved between host and parasite

    PubMed Central

    Seebeck, Thomas; Sterk, Geert Jan; Ke, Hengming

    2011-01-01

    Protozoan infections remain a major unsolved medical problem in many parts of our world. A major obstacle to their treatment is the blatant lack of medication that is affordable, effective, safe and easy to administer. For some of these diseases, including human sleeping sickness, very few compounds are available, many of them old and all of them fraught with toxic side effects. We explore a new concept for developing new-generation antiprotozoan drugs that are based on phosphodiesterase (PDE) inhibitors. Such inhibitors are already used extensively in human pharmacology. Given the high degree of structural similarity between the human and the protozoan PDEs, the vast expertise available in the human field can now be applied to developing disease-specific PDE inhibitors as new antiprotozoan drugs. PMID:21859303

  12. Acute hypoxia modifies cAMP levels induced by inhibitors of phosphodiesterase-4 in rat carotid bodies, carotid arteries and superior cervical ganglia

    PubMed Central

    Nunes, Ana R; Batuca, Joana R; Monteiro, Emília C

    2010-01-01

    Background and purpose: Phosphodiesterase (PDE) inhibitors are useful to treat hypoxia-related diseases and are used in experiments studying the effects of oxygen on 3′-5′-cyclic adenosine monophosphate (cAMP) production. We studied the effects of acute hypoxia on cAMP accumulation induced by PDE inhibitors in oxygen-specific chemosensors, the carotid bodies (CBs) and in non-chemosensitive CB-related structures: carotid arteries (CAs) and superior cervical ganglia (SCG). Experimental approach: Concentration–response curves for the effects of a non-specific PDE inhibitor [isobutylmethylxanthine (IBMX) ], PDE4 selective inhibitors (rolipram, Ro 20-1724) and a PDE2 selective inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine) on cAMP levels were obtained in normoxic (20% O2/5% CO2) or hypoxic (5% O2/5% CO2) conditions. Key results: Responses to the PDE inhibitors were compatible with the presence of PDE4 in rat CBs, CAs and SCG but in the absence of PDE2 in CAs and CBs. Acute hypoxia enhanced the effects of IBMX and PDE4 inhibitors on cAMP accumulation in CAs and CBs. In SCG, acute hypoxia reduced cAMP accumulation induced by all the four PDE inhibitors tested. Differences between the effects of Ro 20-1724 and rolipram on cAMP were found in CAs and CBs during hypoxia. Conclusions and implications: The effects of PDE4 inhibitors could be potentiated or inhibited by acute hypoxia depending on the PDE isoforms of the tissue. The similarities between the characterization of PDE4 inhibitors at the CBs and CAs, under normoxia and hypoxia, did not support a specific role for cAMP in the oxygen-sensing machinery at the CB and suggested that no direct CB-mediated, hyperventilatory, adverse effects would be expected with administration of PDE4 inhibitors. PMID:20082613

  13. Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE₁ in mice.

    PubMed

    Galindo-Tovar, Alejandro; Vargas, María Luisa; Kaumann, Alberto J

    2016-02-01

    Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial β1- and β2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 μM). Bay 60-7550 (1 μM), but not EHNA (10 μM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 μM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 μM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal. PMID:26531832

  14. Crystal Structure of the Leishmania Major Phosphodiesterase LmjPDEB1 and Insight into the Design of hte Parasite-Selective Inhibitors

    SciTech Connect

    Wang,H.; Yan, Z.; Geng, J.; Kunz, S.; Seebeck, T.; Ke, H.

    2007-01-01

    Human leishmaniasis is a major public health problem in many countries, but chemotherapy is in an unsatisfactory state. Leishmania major phosphodiesterases (LmjPDEs) have been shown to play important roles in cell proliferation and apoptosis of the parasite. Thus LmjPDE inhibitors may potentially represent a novel class of drugs for the treatment of leishmaniasis. Reported here are the kinetic characterization of the LmjPDEB1 catalytic domain and its crystal structure as a complex with 3-isobutyl-1-methylxanthine (IBMX) at 1.55 Angstroms resolution. The structure of LmjPDEB1 is similar to that of human PDEs. IBMX stacks against the conserved phenylalanine and forms a hydrogen bond with the invariant glutamine, in a pattern common to most inhibitors bound to human PDEs. However, an extensive structural comparison reveals subtle, but significant differences between the active sites of LmjPDEB1 and human PDEs. In addition, a pocket next to the inhibitor binding site is found to be unique to LmjPDEB1. This pocket is isolated by two gating residues in human PDE families, but constitutes a natural expansion of the inhibitor binding pocket in LmjPDEB1. The structure particularity might be useful for the development of parasite-selective inhibitors for the treatment of leishmaniasis.

  15. Update on drug interactions with phosphodiesterase-5 inhibitors prescribed as first-line therapy for patients with erectile dysfunction or pulmonary hypertension.

    PubMed

    Gur, Serap; Kadowitz, Philip J; Gokce, Ahmet; Sikka, Suresh C; Lokman, Utku; Hellstrom, Wayne J G

    2013-02-01

    Phosphodiesterase-5 inhibitors (PDE5i, sildenafil, vardenafil, tadalafil and avanafil) are a first-line medical therapy for erectile dysfunction (ED). In all likelihood, PDE5i usage will increase because sildenafil (Viagra® and Revatio®) and tadalafil (Cialis® and Adcirca®) have recently been recommended as first-line therapy for patients with pulmonary hypertension (PH). PDE5i exhibit higher plasma concentrations when co-administered with cytochrome P (CYP) 3A inhibitors, which influences their side-effect profile. The higher PDE5i plasma concentrations, caused by CYP3A inhibitors, influence the severity and timing of PDE5i drug interactions and require dose adjustment. PDE5i are safe when used with most antihypertensive agents, but co-administration with nitrates or α-blockers can cause severe hypotension and syncope. Dose adjustment is also necessary when PDE5i are co-administered with CYP3A inducers. The combination of oral tadalafil and bosentan (endothelin receptor antagonist) reduces tadalafil levels and requires dose adjustment. Current literature reports a number of interactions between PDE5i and other agents and further studies are needed to expand our knowledge base of these interactions. This review discusses relevant PDE5i drug interactions, including those with CYP 450 inhibitors and inducers which are frequently used during the treatment of ED and PH. PMID:23140258

  16. Synthesis, Molecular Modeling, and Biological Evaluation of Novel Tetrahydro-β-Carboline Hydantoin and Tetrahydro-β-Carboline Thiohydantoin Derivatives as Phosphodiesterase 5 Inhibitors

    PubMed Central

    Abadi, Ashraf H.; Lehmann, Jochen; Piazza, Gary A.; Abdel-Halim, Mohammad; Ali, Mohamed S. M.

    2011-01-01

    Two series of fused tetrahydro-β-carboline hydantoin and tetrahydro-β-carboline thiohydantoin derivatives with a pendant 2,4-dimethoxyphenyl at position 5 were synthesized, and chiral carbons at positions 5 and 11a swing from R,R to R,S, S,R, and S,S. The prepared analogues were evaluated for their capacity to inhibit phosphodiesterase 5 (PDE5) isozyme. The R absolute configuration of C-5 in the β-carboline hydantoin derivatives was found to be essential for the PDE5 inhibition. Chiral carbon derived from amino acid even if of the S configuration (L-tryptophan) may lead to equiactive or more active isomers than those derived from amino acid with the R configuration (D-tryptophan). This expands the horizon from which efficient PDE5 inhibitors can be derived and may offer an economic advantage. The thiohydantoin derivatives were less active than their hydantoin congeners.

  17. (±)-Torreyunlignans A-D, rare 8-9' linked neolignan enantiomers as phosphodiesterase-9A inhibitors from Torreya yunnanensis.

    PubMed

    Cheng, Zhong-Bin; Lu, Xiao; Bao, Jing-Mei; Han, Qing-Hua; Dong, Zhen; Tang, Gui-Hua; Gan, Li-She; Luo, Hai-Bin; Yin, Sheng

    2014-12-26

    (±)-Torreyunlignans A-D (1a/1b-4a/4b), four pairs of new 8-9' linked neolignan enantiomers featuring a rare (E)-2-styryl-1,3-dioxane moiety, were isolated from the trunk of Torreya yunnanensis. The structures were determined by combined spectroscopic and chemical methods, and the absolute configurations were elucidated by ECD calculations. The compounds were screened by using tritium-labeled adenosine 3',5'-cyclic monophosphate ([(3)H]-cGMP) as a substrate for inhibitory affinities against phosphodiesterase-9A (PDE9A), which is a potential target for the treatment of diabetes and Alzheimer's disease. All of the enantiomers exhibited inhibition against PDE9A with IC50 values ranging from 5.6 to 15.0 μM. This is the first report of PDE9A inhibitors from nature. PMID:25495612

  18. Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals.

    PubMed

    Veerman, Johan; van den Bergh, Toine; Orrling, Kristina M; Jansen, Chimed; Cos, Paul; Maes, Louis; Chatelain, Eric; Ioset, Jean-Robert; Edink, Ewald E; Tenor, Hermann; Seebeck, Thomas; de Esch, Iwan; Leurs, Rob; Sterk, Geert Jan

    2016-04-01

    Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC50 values on both TbrPDEB1 (IC50: 4nM) and TbrPDEB2 (IC50: 3nM) (J. Infect. Dis.2012, 206, 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC50 and EC50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease. PMID:26935942

  19. Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2.

    PubMed

    Marchand, Christophe; Abdelmalak, Monica; Kankanala, Jayakanth; Huang, Shar-Yin; Kiselev, Evgeny; Fesen, Katherine; Kurahashi, Kayo; Sasanuma, Hiroyuki; Takeda, Shunichi; Aihara, Hideki; Wang, Zhengqiang; Pommier, Yves

    2016-07-15

    Tyrosyl-DNA phosphodiesterase 2 repairs irreversible topoisomerase II-mediated cleavage complexes generated by anticancer topoisomerase-targeted drugs and processes replication intermediates for picornaviruses (VPg unlinkase) and hepatitis B virus. There is currently no TDP2 inhibitor in clinical development. Here, we report a series of deazaflavin derivatives that selectively inhibit the human TDP2 enzyme in a competitive manner both with recombinant and native TDP2. We show that mouse, fish, and C. elegans TDP2 enzymes are highly resistant to the drugs and that key protein residues are responsible for drug resistance. Among them, human residues L313 and T296 confer high resistance when mutated to their mouse counterparts. Moreover, deazaflavin derivatives show potent synergy in combination with the topoisomerase II inhibitor etoposide in human prostate cancer DU145 cells and TDP2-dependent synergy in TK6 human lymphoblast and avian DT40 cells. Deazaflavin derivatives represent the first suitable platform for the development of potent and selective TDP2 inhibitors. PMID:27128689

  20. Antenatal Maternally-Administered Phosphodiesterase Type 5 Inhibitors Normalize eNOS Expression in the Fetal Lamb Model of Congenital Diaphragmatic Hernia

    PubMed Central

    Shue, Eveline H; Schecter, Samuel C.; Gong, Wenhui; Etemadi, Mozziyar; Johengen, Michael; Iqbal, Corey; Derderian, S. Christopher; Oishi, Peter; Fineman, Jeffrey R.; Miniati, Doug

    2013-01-01

    Purpose Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. Methods CDH were created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. Results Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82±12% in Normal-Placebo, 61±5% in CDH-Placebo, 116±6% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105±15% in Normal-Placebo, 82±3% in CDH-Placebo, 158±16% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p = 0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p = 0.0002). Conclusions PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH. PMID:24439578

  1. Phosphodiesterase-5 inhibitors for erectile dysfunction in patients with diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials

    PubMed Central

    Balhara, Yatan Pal Singh; Sarkar, Siddharth; Gupta, Rishab

    2015-01-01

    Background and Aims: Patients with diabetes mellitus frequently experience erectile dysfunction. This systematic review and meta-analysis were conducted to find efficacy and tolerability of phosphodiesterase 5 (PDE5) inhibitors in patients with diabetes mellitus experiencing erectile dysfunction. Methodology: Electronic searches were carried out to identify English language peer-reviewed randomized controlled trials (RCTs), which reported clinical efficacy of any PDE5 inhibitor in patients with diabetes mellitus having erectile dysfunction. Effect sizes were computed using Cohen's d, and I2-test was used to assess heterogeneity. Pooled mean effect sizes were computed using random-effects model. Number needed to treat (NNT), and the adverse event rates were computed. Results: The systematic review included a total of 17 studies yielding 25 comparisons. Three studies were open RCTs while others were double-blind RCTs. The pooled mean effect size of any PDE5 inhibitor over placebo was 0.926 (95% confidence intervals [CI]: 0.864-0.987; I2 =26.3). The pooled mean effect size for sildenafil was 1.198 (CI: 1.039-1.357; I2 =0), for tadalafil was 0.910 (CI: 0.838-0.981; I2 =33.6), and for vardenafil was 0.678 (CI: 0.627-0.729; I2 =0). In pooled analysis, the NNT for sildenafil, tadalafil, vardenafil and any PDE5 inhibitor was 2.4, 2.6, 4.1 and 3.0 respectively. The most common side effects were headache, flushing, and nasal congestion. Conclusions: PDE5 inhibitors are effective and safe medications for the treatment of sexual dysfunction in patients with diabetes mellitus experiencing erectile dysfunction. PMID:26180759

  2. One step N-glycosylation by filamentous fungi biofilm in bioreactor of a new phosphodiesterase-3 inhibitor tetrazole.

    PubMed

    de Melo Souza, Paula L; Arruda, Evilanna L; Pazini, Francine; Menegatti, Ricardo; Vaz, Boniek G; Lião, Luciano M; de Oliveira, Valéria

    2016-07-01

    An efficient and rapid process for N-glycosylation of 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole-LQFM 021 (1), a new synthetic derivative of pyrazole with phosphodiesterase-3 (PDE-3) inhibitory action, vasorelaxant activity and low toxicity catalyzed by filamentous fungi biofilm in bioreactor was successfully developed. A maximum N-glycosyl yield of 68% was obtained with Cunninghamella echinulata ATCC 9244 biofilm in bioreactor with conditions of 25mgml(-1) of 1 in PDSM medium at 28°C for 96h. After extraction with ethyl acetate, the derivative was identified by Ultrahigh Resolution Mass Spectrometry and (1)H-(13)C HSQC/HMBC. PMID:27209234

  3. Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors.

    PubMed

    Claffey, Michelle M; Helal, Christopher J; Verhoest, Patrick R; Kang, Zhijun; Fors, Kristina S; Jung, Stanley; Zhong, Jiaying; Bundesmann, Mark W; Hou, Xinjun; Lui, Shenping; Kleiman, Robin J; Vanase-Frawley, Michelle; Schmidt, Anne W; Menniti, Frank; Schmidt, Christopher J; Hoffman, William E; Hajos, Mihaly; McDowell, Laura; O'Connor, Rebecca E; Macdougall-Murphy, Mary; Fonseca, Kari R; Becker, Stacey L; Nelson, Frederick R; Liras, Spiros

    2012-11-01

    Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF. PMID:23025719

  4. A cAMP Biosensor-Based High-Throughput Screening Assay for Identification of Gs-Coupled GPCR Ligands and Phosphodiesterase Inhibitors.

    PubMed

    Vedel, Line; Bräuner-Osborne, Hans; Mathiesen, Jesper Mosolff

    2015-08-01

    Cyclic adenosine 3',5'-monophosphate (cAMP) is an important second messenger, and quantification of intracellular cAMP levels is essential in studies of G protein-coupled receptors (GPCRs). The intracellular cAMP levels are regulated by the adenylate cyclase (AC) upon activation of either Gs- or Gi-coupled GPCRs, which leads to increased or decreased cAMP levels, respectively. Here we describe a real-time Förster resonance energy transfer (FRET)-based cAMP high-throughput screening (HTS) assay for identification and characterization of Gs-coupled GPCR ligands and phosphodiesterase (PDE) inhibitors in living cells. We used the β2-adrenergic receptor (β(2)AR) as a representative Gs-coupled receptor and characterized two cell lines with different expression levels. Low receptor expression allowed detection of desensitization kinetics and delineation of partial agonism, whereas high receptor expression resulted in prolonged signaling and enabled detection of weak partial agonists and/or ligands with low potency, which is highly advantageous in large HTS settings and hit identification. In addition, the assay enabled detection of β(2)AR inverse agonists and PDE inhibitors. High signal-to-noise ratios were also observed for the other representative Gs-coupled GPCRs tested, GLP-1R and GlucagonR. The FRET-based cAMP biosensor assay is robust, reproducible, and inexpensive with good Z factors and is highly applicable for HTS. PMID:25851033

  5. Synergistic effect between 5-HT4 receptor agonist and phosphodiesterase 4-inhibitor in releasing acetylcholine in pig gastric circular muscle in vitro.

    PubMed

    Lefebvre, Romain A; Van Colen, Inge; Pauwelyn, Vicky; De Maeyer, Joris H

    2016-06-15

    5-HT4 receptor agonists have a gastroprokinetic effect by facilitating acetylcholine release from cholinergic nerves innervating gastrointestinal smooth muscle. The role of phosphodiesterase (PDE) 4 in the signal transduction pathway of the 5-HT4 receptors located on the cholinergic neurons towards the circular muscle layer in pig stomach was investigated by analysis of acetylcholine release. Circular muscle strips were prepared from pig proximal stomach and tritium outflow, induced by electrical field stimulation, was studied as a marker for acetylcholine release after incubation with [(3)H]-choline. The PDE4-inhibitor roflumilast concentration-dependently (0.1-1µM) enhanced the facilitating effect of a submaximally effective concentration of the 5-HT4 receptor agonist prucalopride (0.01µM) on electrically induced acetylcholine release. Roflumilast (0.3µM) enhanced acetylcholine release per se but in the combined presence of roflumilast and prucalopride, acetylcholine release was enhanced more than the sum of the effect of the 2 compounds alone. The 5-HT4 receptor agonist velusetrag concentration-dependently (0.01-0.1µM) enhanced acetylcholine release; the effect of the minimally effective concentration (0.01µM) was significantly enhanced by 1µM of the PDE4-inhibitor rolipram, again to a level higher than the sum of the effect of the 2 compounds alone. The synergistic effect between 5-HT4 receptor agonists and PDE4-inhibitors demonstrates that the intracellular pathway of the 5-HT4 receptors located on cholinergic neurons towards pig gastric circular muscle is controlled by PDE4. Combining a 5-HT4 receptor agonist with a PDE4-inhibitor might thus enhance its gastroprokinetic effect. PMID:27060014

  6. Thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives: Structure-activity relationships of selective nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) inhibitors.

    PubMed

    Lee, Sang-Yong; Perotti, Arianna; De Jonghe, Steven; Herdewijn, Piet; Hanck, Theodor; Müller, Christa E

    2016-07-15

    Ecto-nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) is the most important member of the NPP family, which consists of seven closely related proteins (NPP1-NPP7). This glycoprotein is a membrane-associated or secreted enzyme, which catalyzes the hydrolysis of a wide range of phosphodiester bonds, e.g., in nucleoside triphosphates, dinucleotides and nucleotide sugars. NPP1 plays a crucial role in various physiological functions including bone mineralization, soft-tissue calcification, and insulin receptor signaling. Recently, an upregulated expression of NPP1 has been observed in astrocytic brain cancers. Therefore, NPP1 has been proposed as a novel drug target for the treatment of glioblastoma. Despite their therapeutic potential, only few NPP1 inhibitors have been reported to date, which are in most cases non- or only moderately selective. The best investigated NPP1 inhibitors so far are nucleotide derivatives and analogs, however they are not orally bioavailable due to their high polarity. We identified thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives as a new class of NPP1 inhibitors with drug-like properties. Among the 25 derivatives investigated in the present study, 2-[(5-iodo-2-furanyl)methylene]thiazolo[3,2-a]benzimidazol-3(2H)-one (17) was found to be the most potent NPP1 inhibitor with a Ki value of 467nM versus ATP as a substrate and an un-competitive mechanism of inhibition. Compound 17 did not inhibit other human ecto-nucleotidases, including NTPDase1 (CD39), NTPDases2-3, NPP2, NPP3, tissue-nonspecific alkaline phosphatase (TNAP), and ecto-5'-nucleotidase (eN, CD73), and is thus highly selective for NPP1. PMID:27265686

  7. Pregnancy induces a modulation of the cAMP phosphodiesterase 4-conformers ratio in human myometrium: consequences for the utero-relaxant effect of PDE4-selective inhibitors.

    PubMed

    Méhats, C; Tanguy, G; Paris, B; Robert, B; Pernin, N; Ferré, F; Leroy, M J

    2000-02-01

    The inhibitory impacts of RP 73401, a phosphodiesterase type 4 (PDE4) selective inhibitor of the second generation, versus rolipram, the prototypal PDE4 inhibitor, were evaluated and compared on cAMP phosphodiesterase (PDE) activity and contractility of the myometrium in nonpregnant and pregnant women. In enzymatic studies, RP 73401 and rolipram inhibited the cAMP PDE activity with significantly greater maximal efficiency in the myometrium of pregnant compared with nonpregnant women (75 versus 55%; P <.05). Although myometrial PDE4 presented a single class of interaction with RP 73401 [pD(2) (-log [IC(50)]) = -8.2], it exhibited at least two classes of interaction with rolipram (pD(2) = -8.2 and -5.6). In the myometrium of pregnant versus nonpregnant women, rolipram is significantly more efficacious in the concentration range >0.01 to 100 microM (P <.01), whereas no difference was observed for the concentration range <0.01 microM. In contractility studies, RP 73401 was equally effective in relaxing myometrial strips from both nonpregnant and pregnant women (pD(2) = -8.8). Conversely, the ability of rolipram to inhibit contractions of the myometrium in pregnant women was significantly lower (pD(2) = -7.2) compared with that in nonpregnant women (pD(2) = -8.2; P <.01). Concomitantly, in the myometrium of pregnant women, a rise in immunoreactive PDE4B2 signal was detected, whereas the PDE4D3 signal was less intense. These results demonstrate that parallel to an accumulation of PDE4B2 isoform, a modification in the ratio of PDE4 conformers HPDE4 and LPDE4 (conformer that binds rolipram with high and low affinity, respectively) occurs in the myometrium of near-term pregnant women with an increase of LPDE4 functionally implicated in the contractile process. Such modifications provide a strong rationale to propose LPDE4 as potential pharmacologic targets for the design of new tocolytic treatments. PMID:10640323

  8. Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective

    PubMed Central

    Abadi, Ashraf H.; Gary, Bernard D.; Tinsley, Heather N.; Piazza, Gary A.; Abdel-Halim, Mohammad

    2016-01-01

    The synthesis of novel tadalafil analogues in which the benzodioxole moiety is replaced by 2-bromophenyl; the chiral carbons swing from R,R to R,S, S,R and S,S; the piperazinedione ring is maintained or reduced to the 5-membered imidazolidinedione or thioxoimidazolinone is described. The prepared analogues were evaluated for their capacity to inhibit the cyclic guanosine monophosphate (cGMP) selective phosphodiesterase 5 (PDE5) isozyme and the growth of human HT-29 colon adenocarcinoma cells. The R absolute configuration of C-5 in the β-carboline-hydantoin and C-6 in the β-carboline-piperazinedione derivatives was found to be essential for the PDE5 inhibition. In addition, tadalafil analogues that were synthesized from L-tryptophan were more active than those derived from D-tryptophan, which is of economic value and expands the horizon for the discovery of new carbolines as PDE5 inhibitors. While some analogues displayed potent tumor cell growth inhibitory activity, there was no apparent correlation with their PDE5 inhibitory activity, which leads us to conclude that other PDE isozymes or PDE5 splice variants may be involved. PMID:20206015

  9. Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective.

    PubMed

    Abadi, Ashraf H; Gary, Bernard D; Tinsley, Heather N; Piazza, Gary A; Abdel-Halim, Mohammad

    2010-04-01

    The synthesis of novel tadalafil analogues in which the benzodioxole moiety is replaced by 2-bromophenyl; the chiral carbons swing from R,R to R,S, S,R and S,S; the piperazinedione ring is maintained or reduced to the 5-membered imidazolidinedione or thioxoimidazolinone is described. The prepared analogues were evaluated for their capacity to inhibit the cyclic guanosine monophosphate (cGMP) selective phosphodiesterase 5 (PDE5) isozyme and the growth of human HT-29 colon adenocarcinoma cells. The R absolute configuration of C-5 in the beta-carboline-hydantoin and C-6 in the beta-carboline-piperazinedione derivatives was found to be essential for the PDE5 inhibition. In addition, tadalafil analogues that were synthesized from l-tryptophan were more active than those derived from d-tryptophan, which is of economic value and expands the horizon for the discovery of new carbolines as PDE5 inhibitors. While some analogues displayed potent tumor cell growth inhibitory activity, there was no apparent correlation with their PDE5 inhibitory activity, which leads us to conclude that other PDE isozymes or PDE5 splice variants may be involved. PMID:20206015

  10. A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fibre nerves.

    PubMed

    Wakita, Hisashi; Ohkuro, Masayoshi; Ishii, Naoto; Hishinuma, Ieharu; Shirato, Manabu

    2015-03-01

    E6005, a potent, selective phosphodiesterase (PDE) 4 inhibitor, has been developed as a novel topical agent of atopic dermatitis (AD). It has been shown to inhibit itching in patients with AD as well in mouse models. To study the mechanism underlying the anti-pruritic effect of E6005, we examined its effect on the activation of dorsal root ganglion (DRG) neurons associated with the itch sensation. Depolarization of DRG neurons by a transient receptor potential vanilloid 1 (TRPV 1) activator, capsaicin was attenuated by E6005 as well as by a 3',5'-cyclic adenosine monophosphate (cAMP) elevator, forskolin. E6005 elevated intracellular levels of cAMP in DRG cells. Taken together, these results suggest that E6005 suppresses TRPV1-mediated C-fibre depolarization through elevation of cAMP levels, thereby exerting an anti-pruritic effect. Thus, E6005 shows the potential to be a new agent for managing pruritus in various skin disorders, including AD. PMID:25431172

  11. Design, Synthesis, and Structure-Activity Relationship, Molecular Modeling, and NMR Studies of a Series of a Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors

    SciTech Connect

    Zheng, S.; Kaur, G; Wang, H; Li, M; MacNaughtan, M; Yang, X; Reid, S; Prestegard, J; Wang, B; et. al.

    2008-01-01

    Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC{sub 50} values. The most potent compounds have IC50 values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.

  12. A review of cilostazol, a phosphodiesterase inhibitor, and its role in preventing both coronary and peripheral arterial restenosis following endovascular therapy.

    PubMed

    Dindyal, Shiva; Kyriakides, Constantinos

    2009-01-01

    Systemic vascular disease is the greatest cause of mortality in the western world. Treatment options have been preventative with medical therapy or curative with surgical bypass. Recently, there has been an increase in the use and popularity of minimally invasive endovascular techniques, particularly angioplasty and stent insertions. The short-term results of these techniques have been demonstrated to be superior in a number of studies when compared with conventional surgery, which itself carries high mortality and morbidity. The long-term outcomes of endovascular treatments have not been as impressive, due to vascular restenosis caused mainly by intimal hyperplasia. There have been a large number of studies and therapeutic trials to discover a solution to restenosis, but to date success has not been reached. Cilostazol is a phosphodiesterase inhibitor licensed for treating patients suffering from intermittent claudication. Recent clinical trials have shown the effects of cilostazol in also preventing coronary artery restenosis post-endovascular treatments. These results have recently been repeated for peripheral vascular stents. This review discusses the pharmacology of cilostazol, peripheral vascular disease, mechanisms of intimal hyperplasia causing vascular restenosis. We also discuss the use of cilostazol and other current patents of novel targets and therapeutics, for preventing restenosis of both coronary and peripheral arterial disease following endovascular therapies. PMID:19149700

  13. Phosphodiesterase type 5 inhibitor administered immediately after radical prostatectomy temporarily increases the need for incontinence pads, but improves final continence status

    PubMed Central

    Yamashita, Shinichi; Ito, Akihiro; Kawasaki, Yoshihide; Izumi, Hideaki; Kawamorita, Naoki; Adachi, Hisanobu; Mitsuzuka, Koji; Arai, Yoichi

    2016-01-01

    Purpose To evaluate the effects of phosphodiesterase type 5 inhibitor (PDE5i) on urinary continence recovery after bilateral nerve-sparing radical prostatectomy (BNSRP). Materials and Methods Between 2002 and 2012, 137 of 154 consecutive patients who underwent BNSRP in our institution retrospectively divided into 3 groups that included patients taking PDE5i immediately after surgery (immediate PDE5i group, n=41), patients starting PDE5i at an outpatient clinic after discharge (PDE5i group, n=56), and patients taking no medication (non-PDE5i group, n=40). Using self-administered questionnaires, the proportion of patients who did not require incontinence pads (pad-free patients) was calculated preoperatively and at 1, 3, 6, 12, 18, and 24 months after BNSRP. Severity of incontinence was determined based on the pad numbers and then compared among the 3 groups. Results Proportions of pad-free patients and severity of incontinence initially deteriorated in all of the groups to the lowest values soon after undergoing BNSRP, with gradual improvement noted thereafter. The deterioration was most prominent in the immediate PDE5i group. As compared to the non-PDE5i group, both the PDE5i and immediate PDE5i groups exhibited a better final continence status. Conclusions PDE5i improves final continence status. However, administration of PDE5i immediately after surgery causes a distinct temporary deterioration in urinary incontinence.

  14. Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.

    PubMed

    Yoshikawa, Masato; Kamisaki, Haruhi; Kunitomo, Jun; Oki, Hideyuki; Kokubo, Hironori; Suzuki, Akihiro; Ikemoto, Tomomi; Nakashima, Kosuke; Kamiguchi, Naomi; Harada, Akina; Kimura, Haruhide; Taniguchi, Takahiko

    2015-11-15

    Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice. PMID:26494583

  15. Synthesis of a tritium-labeled indolidan analogue and its use as a radioligand for phosphodiesterase-inhibitor cardiotonic binding sites

    SciTech Connect

    Robertson, D.W.; Krushinski, J.H.; Utterback, B.G.; Kauffman, R.F.

    1989-07-01

    We have radiolabeled a structural analogue of indolidan, a potent phosphodiesterase-inhibitor cardiotonic, to permit biochemical studies regarding the interaction of this class of drugs with their pharmacological receptor. (/sup 3/H)-LY186126 (1,3-dihydro-3,3-dimethyl-1-(/sup 3/H3)methyl-5-(1,4,5,6-tetrahydro-4-me thyl-6- oxo-3-pyridazinyl)-2H-indol-2-one; (/sup 3/H)-3) was selected as a synthetic target because of its potency as a cardiotonic and the ability to readily incorporate three tritia via the indolone N-CH3 substituent. Alkylation of a desmethyl precursor with tritium-labeled iodomethane resulted in (/sup 3/H)-3 with a radiochemical purity of 98% and a specific activity of 79.2 Ci/mmol. This radioligand binds with high affinity to myocardial membrane vesicles. The binding was saturable, and Kd and Bmax values of 4.1 nM and 383 fmol/mg protein were obtained. A series of indolidan congeners displaced (/sup 3/H)-3 bound to myocardial vesicles, and Ki values for inhibition of binding were highly correlated with canine inotropic ED50 values, suggesting the specific binding of (/sup 3/H)-3 to cardiac vesicles is pharmacologically relevant.

  16. Simultaneous Detection of Three Phosphodiesterase Type 5 Inhibitors and Eight of Their Analogs in Lifestyle Products and Screening for Adulterants by High-Performance Thin-Layer Chromatography.

    PubMed

    Do, Tiên T K; Theocharis, Grigorios; Reich, Eike

    2015-01-01

    An HPTLC method is proposed to permit effective screening for the presence of three phosphodiesterase type 5 inhibitors (PDE5-Is; sildenafil, vardenafil, and tadalafil) and eight of their analogs (hydroxyacetildenafil, homosildenafil, thiohomosildenafil, acetildenafil, acetaminotadalafil, propoxyphenyl hydroxyhomosildenafil, hydroxyhomosildenafil, and hydroxythiohomosildenafil) in finished products, including tablets, capsules, chocolate, instant coffee, syrup, and chewing gum. For all the finished products, the same simple sample preparation may be applied: ultrasound-assisted extraction in 10 mL methanol for 30 min followed by centrifugation. The Rf values of individual HPTLC bands afford preliminary identification of potential PDE5-Is. Scanning densitometry capabilities enable comparison of the unknown UV spectra with those of known standard compounds and allow further structural insight. Mass spectrometric analysis of the material derived from individual zones supplies an additional degree of confidence. Significantly, the proposed screening technique allows focus on the already known PDE5 Is and provides a platform for isolation and chemical categorization of the newly-synthesized analogs. Furthermore, the scope could be expanded to other therapeutic categories (e.g., analgesics, antidiabetics, and anorexiants) that are occasionally coadulterated along with the PDE5-Is. The method was successfully applied to screening of 45 commercial lifestyle products. Of those, 31 products tested positive for at least one illegal component (sildenafil, tadalafil, propoxyphenyl hydroxyhomosildenafil, or dimethylsildenafil). PMID:26525240

  17. Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.

    PubMed

    Li, Peng; Zheng, Hailin; Zhao, Jun; Zhang, Lei; Yao, Wei; Zhu, Hongwen; Beard, J David; Ida, Koh; Lane, Weston; Snell, Gyorgy; Sogabe, Satoshi; Heyser, Charles J; Snyder, Gretchen L; Hendrick, Joseph P; Vanover, Kimberly E; Davis, Robert E; Wennogle, Lawrence P

    2016-02-11

    A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders. PMID:26789933

  18. GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization.

    PubMed

    Tralau-Stewart, Cathy J; Williamson, Richard A; Nials, Anthony T; Gascoigne, Michele; Dawson, John; Hart, Graham J; Angell, Anthony D R; Solanke, Yemisi E; Lucas, Fiona S; Wiseman, Joanne; Ward, Peter; Ranshaw, Lisa E; Knowles, Richard G

    2011-04-01

    Oral phosphodiesterase (PDE) 4 inhibitors such as roflumilast have established the potential of PDE4 inhibition for the treatment of respiratory diseases. However, PDE4 inhibitor efficacy is limited by mechanism-related side effects such as emesis and nausea. Delivering the inhibitor by the inhaled route may improve therapeutic index, and we describe 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy) phenyl]amino}-3-quinolinecarboxamide (GSK256066), an exceptionally high-affinity inhibitor of PDE4 designed for inhaled administration. GSK256066 is a slow and tight binding inhibitor of PDE4B (apparent IC(50) 3.2 pM; steady-state IC(50) <0.5 pM), which is more potent than any previously documented compound, for example, roflumilast (IC(50) 390 pM), tofimilast (IC(50) 1.6 nM), and cilomilast (IC(50) 74 nM). Consistent with this, GSK256066 inhibited tumor necrosis factor α production by lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes with 0.01 nM IC(50) (compared with IC(50) values of 5, 22, and 389 nM for roflumilast, tofimilast, and cilomilast, respectively) and by LPS-stimulated whole blood with 126 pM IC(50). GSK256066 was highly selective for PDE4 (>380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and >2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial high-affinity rolipram binding site ratio (>17). When administered intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED(50) values of 1.1 μg/kg (aqueous suspension) and 2.9 μg/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED(50) 9.3 μg/kg). Thus, GSK256066 has been demonstrated to have exceptional potency in vitro and in vivo and is being clinically investigated as a treatment for chronic obstructive pulmonary disease. PMID:21205923

  19. Phosphodiesterase Type 5 Inhibitors and Risk of Malignant Melanoma: Matched Cohort Study Using Primary Care Data from the UK Clinical Practice Research Datalink

    PubMed Central

    Langan, Sinéad M.; Douglas, Ian J.; Smeeth, Liam; Bhaskaran, Krishnan

    2016-01-01

    Background Laboratory evidence suggests that reduced phosphodiesterase type 5 (PDE5) expression increases the invasiveness of melanoma cells; hence, pharmacological inhibition of PDE5 could affect melanoma risk. Two major epidemiological studies have investigated this and come to differing conclusions. We therefore aimed to investigate whether PDE5 inhibitor use is associated with an increased risk of malignant melanoma, and whether any increase in risk is likely to represent a causal relationship. Methods and Findings We conducted a matched cohort study using primary care data from the UK Clinical Practice Research Datalink. All men initiating a PDE5 inhibitor and with no prior cancer diagnosis were identified and matched on age, diabetes status, and general practice to up to four unexposed controls. Ever use of a PDE5 inhibitor and time-updated cumulative number of PDE5 inhibitor prescriptions were investigated as exposures, and the primary outcome was malignant melanoma. Basal cell carcinoma, solar keratosis, and colorectal cancer were investigated as negative control outcomes to exclude bias. Hazard ratios (HRs) were estimated from Cox models stratified by matched set and adjusted for potential confounders. 145,104 men with ≥1 PDE5 inhibitor prescription, and 560,933 unexposed matched controls were included. In total, 1,315 incident malignant melanoma diagnoses were observed during 3.44 million person-years of follow-up (mean 4.9 y per person). After adjusting for potential confounders, there was weak evidence of a small positive association between PDE5 inhibitor use and melanoma risk (HR = 1.14, 95% CI 1.01–1.29, p = 0.04). A similar increase in risk was seen for the two negative control outcomes related to sun exposure (HR = 1.15, 95% CI 1.11–1.19, p < 0.001, for basal cell carcinoma; HR = 1.21, 95% CI 1.17–1.25, p < 0.001, for solar keratosis), but there was no increased risk for colorectal cancer (HR = 0.91, 95% CI 0.85–0.98, p = 0.01). There was

  20. Icariin, a phosphodiesterase-5 inhibitor, improves learning and memory in APP/PS1 transgenic mice by stimulation of NO/cGMP signalling.

    PubMed

    Jin, Feng; Gong, Qi-Hai; Xu, Ya-Sha; Wang, Li-Na; Jin, Hai; Li, Fei; Li, Li-Sheng; Ma, Yue-Ming; Shi, Jing-Shan

    2014-06-01

    Phosphodiesterase-5 (PDE5) inhibitors are predominantly used in the treatment of erectile dysfunction, and have been recently shown to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD) through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling by elevating cGMP, which is a secondary messenger involved in processes of neuroplasticity. In the present study, the effects of a PDE5 inhibitor, icarrin (ICA), on learning and memory as well as the pathological features in APP/PS1 transgenic AD mice were investigated. Ten-month-old APP/PS1 transgenic mice overexpressing human amyloid precursor protein (APP695swe) and presenilin 1 (PS1-dE9) were given ICA (30 and 60 mg/kg) or sildenafil (SIL) (2 mg/kg), age-matched wild-type (WT) mice were given ICA (60 mg/kg), and APP/PS1 and WT control groups were given an isovolumic vehicle orally twice a day for four months. Results demonstrated that ICA treatments significantly improved learning and memory of APP/PS1 transgenic mice in Y-maze tasks. The amyloid precursor protein (APP), amyloid-beta (Aβ1-40/42) and PDE5 mRNA and/or protein levels were increased in the hippocampus and cortex of APP/PS1 mice, and ICA treatments decreased these physiopathological changes. Furthermore, ICA-treated mice showed an increased expression of three nitric oxide synthase (NOS) isoforms at both mRNA and protein levels, together with increased NO and cGMP levels in the hippocampus and cortex of mice. These findings demonstrate that ICA improves learning and memory functions in APP/PS1 transgenic mice possibly through the stimulation of NO/cGMP signalling and co-ordinated induction of NOS isoforms. PMID:24513083

  1. The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey.

    PubMed

    Smith, Sean M; Uslaner, Jason M; Cox, Christopher D; Huszar, Sarah L; Cannon, Christopher E; Vardigan, Joshua D; Eddins, Donnie; Toolan, Dawn M; Kandebo, Monika; Yao, Lihang; Raheem, Izzat T; Schreier, John D; Breslin, Michael J; Coleman, Paul J; Renger, John J

    2013-01-01

    Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID:22750078

  2. Activation of wild-type and deltaF508-CFTR by phosphodiesterase inhibitors through cAMP-dependent and -independent mechanisms.

    PubMed

    Al-Nakkash, L; Hwang, T C

    1999-03-01

    The cAMP-dependent activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and its modulation through inhibition of phosphodiesterases (PDE) were studied with the cell-attached patch-clamp technique in Calu-3 cells (expressing endogenous CFTR) and NIH3T3 cells [expressing either wild-type (Wt)-CFTR or DeltaF508-CFTR]. In Calu-3 cells, CFTR current was augmented by increasing concentrations of 8-(4-chlorophenylthio)-adenosine 3', 5'-cyclic monophosphate (CPT-cAMP) and reached a saturating level at >/=60 microM. Varying the forskolin concentration also modulated CFTR activity; 10 microM was maximally effective since supplemental application of 200 microM CPT-cAMP had no additional effect. Activation of CFTR by increasing the cAMP concentration occurs through an increase of the NPo (product of the number of functional channels and the open probability) since the single-channel amplitude remains unchanged. In Calu-3 and NIH3T3-Wt cells, PDE inhibitors, milrinone (100 microM), 8-cyclopentyl-1, 3-dipropylxanthine (CPX, 25 microM), and 3-isobutyl-1-methylxanthine (IBMX, 200 microM), did not enhance CFTR current initially activated with 10 microM forskolin, but each potentiated CFTR activity elicited with a submaximal forskolin concentration (e.g., 100 nM) and prolonged the deactivation of CFTR channel current upon removal of forskolin. Millimolar IBMX increased the NPo of both Wt- and DeltaF508-CFTR even under maximal cAMP stimulation. Quantitatively, these effects of millimolar IBMX on NPo approximate those of genistein, which potentiates the cAMP-dependent CFTR activity via a mechanism that does not involve increases in cellular cAMP. Thus, depending on the concentration, PDE inhibitors may affect CFTR through different mechanisms. PMID:10089568

  3. Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes.

    PubMed

    Dong, Chen; Virtucio, Charlotte; Zemska, Olga; Baltazar, Grober; Zhou, Yasheen; Baia, Diogo; Jones-Iatauro, Shannon; Sexton, Holly; Martin, Shamra; Dee, Joshua; Mak, Yvonne; Meewan, Maliwan; Rock, Fernando; Akama, Tsutomu; Jarnagin, Kurt

    2016-09-01

    Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-α, interleukin (IL)-23, IL-17, interferon-γ, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal

  4. A quantitative comparison of functional and anti-ischaemic effects of the phosphodiesterase-inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts.

    PubMed Central

    Rump, A. F.; Acar, D.; Klaus, W.

    1994-01-01

    1. The functional and anti-ischaemic effects of the phosphodiesterase (PDE)-inhibitors, amrinone, milrinone and levosimendan, a new agent combining PDE-inhibitory with calcium-sensitizing properties, were investigated in rabbit isolated hearts (Langendorff, constant pressure: 70 cmH2O, Tyrode solution, Ca2+ 1.8 mmol l-1, 37 degrees C). Anti-ischaemic effects were studied in electrically-driven hearts (200 beats min-1). Acute regional ischaemia was induced by ligature of a branch of the circumflex coronary artery and quantified from epicardial NADH-fluorescence photography. 2. Cumulative concentration-response curves in spontaneously beating hearts in the presence of isoprenaline (10(-10) M), showed a higher inotropic and coronary vasodilator potency for levosimendan (EC50: 7 x 10(-7) M) compared to milrinone (EC50: 7.7 x 10(-6) M) or amrinone (EC50: 2 x 10(-5) M). Although the maximal coronary dilator activity was similar for the three agents, the maximal inotropic and chronotropic effects were lower for levosimendan than for amrinone or milrinone (P < 0.05). 3. In regionally ischaemic hearts, milrinone (10(-5) M) or levosimendan (5 x 10(-6) M) similarly enhanced the left ventricular pressure (+15-20%) (P < 0.05) and the global coronary flow (+40-50%) (P < 0.05). The epicardial NADH-fluorescence area was significantly diminished by milrinone or levosimendan (-20-30%) (P < 0.05) and there was no significant difference between the anti-ischaemic effects of either agent (P > 0.05). 4. It is concluded that amrinone and milrinone possess similar functional profiles in rabbit isolated hearts and a higher inotropic and chronotropic efficacy than levosimendan.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7921599

  5. cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats

    PubMed Central

    Liu, Xu; Guo, Haibiao; Sayed, Mohammad Daud SOM; Lu, Yang; Yang, Ting; Zhou, Dongsheng; Chen, Zhongming; Wang, Haitao; Wang, Chuang; Xu, Jiangping

    2016-01-01

    Objectives GEBR-7b, a potential phosphodiesterase 4D inhibitor, has been shown to have memory-enhancing effects in rodents. However, it is still unknown whether GEBR-7b also has the antidepressant-like effects in rats. Herein, we examined the potential of GEBR-7b to attenuate depression-like behaviors in the rat model of depression induced by chronic unpredictable stress (CUS). Next, we also investigated the alterations of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) catalytic subunit (PKAca), cAMP response element-binding (CREB), and glutamate transporter 1 (GLT1) levels produced by GEBR-7b in the rats model of depression. Methods Effects of GEBR-7b on CUS (35 days)-induced depression-like behaviors were examined by measuring immobility time in the forced swimming test (FST). Hippocampal cAMP levels were examined by enzyme-linked immunosorbent assay, whereas PKAca, phosphorylation of CREB (pCREB), CREB, and GLT1 in the hippocampus of rats were subjected to Western blot analysis. Results CUS exposure caused a depression-like behavior evidenced by the increased immobility time in FST. Depression-like behavior induced by CUS was accompanied by a significant increased GLT, decreased cAMP, PKAca, pCREB activities in hippocampus. However, repeated GEBR-7b administration significantly reversed CUS-induced depression-like behavior and changes of cAMP/PKA/CREB/GLT1 signaling. No alteration was observed in locomotor activity in open field test. Conclusion These findings indicate that GEBR-7b reversed the depression-like behaviors induced by CUS in rats, which is at least in part mediated by modulating cAMP, PKAca, pCREB, and GLT1 levels in the hippocampus of rats, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by CUS. PMID:26855578

  6. Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: involvement of antioxidant and anti-apoptotic mechanisms

    PubMed Central

    Li, Jianxin; Sun, Jiao; Nadeem, Ahmed; Zhang, Han-Ting; O’ Donnell, James M.; Xu, Ying

    2014-01-01

    Stress occurs in everyday life, but the relationship between stress and the onset or development of depression/anxiety remains unknown. Increasing evidence suggests that the impairment of antioxidant defense and the neuronal cell death are important in the process of emotional disorders. Chronic stress impairs the homeostasis of antioxidants/oxidation, which results in the aberrant stimulation of the cell cycle proteins where cGMP-PKG signaling is thought to have an inhibitory role. Phosphodiesterase 2 (PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala, which may play important roles in the treatment of depression and anxiety. To address the possible effects of PDE2 inhibitors on depression-/anxiety-like behaviors and the underlying mechanisms, Bay 60-7550 (0.75, 1.5 and 3 mg/kg, i.p.) was administered 30 min before chronic stress. The results suggested that Bay 60-7550 not only restored the behavioral changes but also regulated Cu/Zn superoxide dismutase (SOD) levels differentially in hippocampus and amygdala, which were increased in the hippocampus while decreased in the amygdala. It was also significant that Bay 60-7550 regulated the abnormalities of pro- and anti-apoptotic components, such as Bax, Caspase 3 and Bcl-2, and the indicator of PKG signaling characterized by pVASPser239, in these two brain regions. The results suggested that Bay 60-7550 is able to alleviate oxidative stress and mediate part of the apoptotic machinery in neuronal cells possibly through SOD-cGMP/PKG-anti-apoptosis signaling and that inhibition of PDE2 may represent a novel therapeutic target for psychiatric disorders, such as depression and anxiety. PMID:24694839

  7. Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial.

    PubMed

    Nemoto, Osamu; Hayashi, Nobukazu; Kitahara, Yasumi; Furue, Masutaka; Hojo, Seiichiro; Nomoto, Maiko; Shima, Satoshi

    2016-08-01

    This exploratory study was designed to evaluate the safety and efficacy profile of the topical phosphodiesterase 4 inhibitor E6005 in Japanese children with mild-to-moderate atopic dermatitis. The present randomized, multicenter study included 62 patients who were treated with 0.05% E6005, 0.2% E6005 or vehicle ointment twice daily for 2 weeks. Safety and pharmacokinetics were assessed with a focus on the occurrence of adverse events and the whole blood concentrations of E6005 and its metabolite. Exploratory efficacy evaluations included assessments of lesion severity and pruritus score. The 2-week application of topical E6005 was safe and well tolerated with no cutaneous adverse events. The whole blood concentration of E6005 was quantified in only one subject receiving 0.2% E6005 treatment, while its major metabolite was undetectable. The 0.2% E6005 group showed a greater decrease in the severity score than the vehicle group (-45.94% vs -32.26%), although this difference was not statistically significant. Similarly, the treatment success rate according to the investigator's global assessment of the total application sites was higher in the 0.2% E6005 group than in the vehicle group (34.4% vs 20.0%). Moreover, the 0.2% E6005 group showed a greater decrease in the pruritus score than the vehicle group (-37.5% vs -6.7%) in a predefined subpopulation. The efficacy of 0.05% E6005 treatment was comparable to that of vehicle treatment. These results suggest that topical 0.2% E6005 treatment is safe and effective in children with atopic dermatitis, although further large confirmatory clinical trials are warranted. PMID:26703371

  8. Let’s rethinking about the safety of phosphodiesterase type 5 inhibitor in the patients with erectile dysfunction after radical prostatectomy

    PubMed Central

    Kim, Su Jin; Kim, Ju Ho; Chang, Hyun-Kyung; Kim, Khae Hawn

    2016-01-01

    As the radical prostatectomy (RP) for the patient diagnosed as localized prostate cancer has been increasing, erectile dysfunction (ED) associated with RP is increased and ED after RP is a significant risk factor to reduce the quality of life for the patient after RP. Therefore, the treatment concept called penile rehabilitation was introduced and phosphodiesterase type 5 inhibitor (PDE5I) is used widely for the prostate cancer patient after RP. Generally PDE5I is considered as safe and effective drug for the prostate cancer patient after RP. Recently, a report against the general opinion that PDE5I use is safe in the patient with prostate cancer was reported and the analysis of 5-yr biochemical recurrence-free survival after RP between the PDE5I users and non-PDE5I users after bilateral nerve sparing RP showed decreased 5-yr biochemical recurrence-free survival in the PDE5I users. In addition, a longitudinal cohort study reported that sildenafil, a kind of PDE5I, use might be associated with the development of melanoma and this result suggested the possibility of adverse effect of PDE5I on some kinds of cancers as well as prostate cancer. Moreover, the studies to evaluate the influence of nitric oxide (NO) and guanosine monophosphate (cGMP) signaling pathway associated with PDE5 showed both cancer reduction and cancer development. Therefore, the role of NO and cGMP signaling pathway in cancer was reviewed based on the previous studies and suggested the necessity of further clinical studies concerning about the safety of PDE5I in prostate cancer. PMID:27419107

  9. A meta-regression evaluating the effectiveness and prognostic factors of oral phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction.

    PubMed

    Yuan, Jin-Qiu; Mao, Chen; Yang, Zu-Yao; Fu, Xiao-Hong; Wong, Samuel Y; Tang, Jin-Ling

    2016-01-01

    The effectiveness of phosphodiesterase type 5 inhibitors (PDE5-Is) for erectile dysfunction (ED) varies considerably among trials, but available studies investigating the factors that affect the effectiveness are few and findings are not consistent. A systematic search was performed in PubMed, Cochrane Library, and EMBASE to identify randomized controlled trials comparing PDE5-Is with placebo for the treatment of ED. The methodological quality of included studies was assessed by the Cochrane Collaboration's tool for assessing risk of bias. The associations between prespecified study-level factors and effectiveness were tested by a random effects meta-regression model. This study included 93 trials with 26 139 patients. When all PDE5-Is were grouped together, Caucasian ethnicity was associated with 15.636% (95% confidence interval [CI]: 0.858% to 32.579%) increase in risk ratio (RR) for Global Assessment Questionnaire question-1 (GAQ-1), and 1.473 (95% CI: 0.406 to 2.338) score increase in mean difference (MD) for posttreatment International Index of Erectile Function-Erectile Function domain score (IIEF-EF), compared to Asian ethnicity. A one-score increase in baseline IIEF-EF was associated with -5.635% (95% CI: -9.120% to -2.017%) reduction in RR for GAQ-1, and -0.229 (95% CI: -0.425 to -0.042) score decrease in MD for posttreatment IIEF-EF. In conclusion, PDE5-Is are more effective in Caucasians than Asians, and in patients with more severe ED. PMID:25966626

  10. The Efficacy of Medical Treatment of Peyronie's Disease: Potassium Para-Aminobenzoate Monotherapy vs. Combination Therapy with Tamoxifen, L-Carnitine, and Phosphodiesterase Type 5 Inhibitor

    PubMed Central

    Park, Tae Yong; Jeong, Hyeong Guk; Park, Jong Jin; Chae, Ji Yun; Kim, Jong Wook; Oh, Mi Mi; Park, Hong Seok; Kim, Je Jong

    2016-01-01

    Purpose This study was designed to evaluate the efficacy of medical treatment of Peyronie's disease. Materials and Methods A total of 109 patients with Peyronie's disease who had been treated from January 2011 to December 2014 were retrospectively reviewed in this study. Forty-four patients (Group 1) were treated with 12 mg of potassium para-aminobenzoate daily. Sixty-five patients (Group 2) were treated with combination therapy: tamoxifen (20 mg) and acetyl-L-carnitine (300 mg) twice daily in addition to a phosphodiesterase type 5 inhibitor. Ability to perform sexual intercourse, pain during erection, size of plaque, and penile curvature angle were assessed. Results In Group 1, 30 of 44 patients (68.2%) discontinued treatment within 12 weeks, while 5 patients (7.7%) in Group 2 discontinued treatment. Pain during erection and plaque size were improved in both groups but showed no statistical difference due to the high dropout rate in Group 1. In both groups, penile curvature was improved, but demonstrated no statistical difference between the treatment groups. However, combination therapy demonstrated a better response rate in patients whose penile curvature angle was less than 30° (44.4% vs. 79.1%, p=0.048). The rate of successful sexual intercourse was significantly higher in Group 2 (42.8% vs. 78.3%, p=0.034). The number of patients who underwent surgical correction despite medical treatment was significantly higher in Group 1 (35.7% vs. 13.3%, p=0.048). Conclusions Early medical combination therapy in Peyronie's disease may present better results in patients whose curvature angle is less than 30°. PMID:27169128

  11. Systematic review and meta-analysis on phosphodiesterase 5 inhibitors and α-adrenoceptor antagonists used alone or combined for treatment of LUTS due to BPH

    PubMed Central

    Wang, Xing-Huan; Wang, Xiao; Shi, Ming-Jun; Li, Sheng; Liu, Tao; Zhang, Xin-Hua

    2015-01-01

    The aim of this systematic review is to determine the comparative effectiveness and safety of phosphodiesterase 5 inhibitors (PDE5-Is) and α-blockers used alone or combined for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). An electronic search of PubMed, Cochrane Library and Embase up to January 2014 was performed to identify randomized controlled trials comparing the efficacy and safety of PDE5-Is and α-blockers for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia, which assessed IPSS score, maximum flow rate, postvoided residual urine, quality of life and Erectile Function (IIEF) score as outcomes. Data were analyzed by fixed or random effect models using Cochrane Collaboration review manager software. A total of 12 studies were included. Our novel data demonstrated that there was a trend that α-blockers were more efficacious than PDE5-Is on decreasing IPSS score and increasing maximum flow rate. α-blockers were significantly more effective than PDE5-Is on reduction of postvoided residual urine with a mean difference of 3.67 (95% CI 1.56 to 5.77, P = 0.0006) and PDE5-Is showed greater effect than α-blockers on increasing IIEF score with a mean difference of 9.82 (95% CI 3.80 to 15.85, P = 0.001). In conclusion, our novel data demonstrated that PDE5-Is plus ABs ranked the highest on the improvement of LUTS/BPH. PDE5-Is monotherapy was also effective in this kind of disorder except less reduction of PVR than ABs. In addition, both combined- or mono-therapy were safe. PMID:25994648

  12. CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration.

    PubMed

    Moretto, Nadia; Caruso, Paola; Bosco, Raffaella; Marchini, Gessica; Pastore, Fiorella; Armani, Elisabetta; Amari, Gabriele; Rizzi, Andrea; Ghidini, Eleonora; De Fanti, Renato; Capaldi, Carmelida; Carzaniga, Laura; Hirsch, Emilio; Buccellati, Carola; Sala, Angelo; Carnini, Chiara; Patacchini, Riccardo; Delcanale, Maurizio; Civelli, Maurizio; Villetti, Gino; Facchinetti, Fabrizio

    2015-03-01

    This study examined the pharmacologic characterization of CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide], a novel phosphodiesterase (PDE)4 inhibitor designed for treating pulmonary inflammatory diseases via inhaled administration. CHF6001 was 7- and 923-fold more potent than roflumilast and cilomilast, respectively, in inhibiting PDE4 enzymatic activity (IC50 = 0.026 ± 0.006 nM). CHF6001 inhibited PDE4 isoforms A-D with equal potency, showed an elevated ratio of high-affinity rolipram binding site versus low-affinity rolipram binding site (i.e., >40) and displayed >20,000-fold selectivity versus PDE4 compared with a panel of PDEs. CHF6001 effectively inhibited (subnanomolar IC50 values) the release of tumor necrosis factor-α from human peripheral blood mononuclear cells, human acute monocytic leukemia cell line macrophages (THP-1), and rodent macrophages (RAW264.7 and NR8383). Moreover, CHF6001 potently inhibited the activation of oxidative burst in neutrophils and eosinophils, neutrophil chemotaxis, and the release of interferon-γ from CD4(+) T cells. In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast, UK-500,001 [2-(3,4-difluorophenoxy)-5-fluoro-N-((1S,4S)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide], and cilomilast, and it was comparable to GSK256066 [6-((3-(dimethylcarbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide]. When administered intratracheally to rats as a micronized dry powder, CHF6001 inhibited liposaccharide-induced pulmonary neutrophilia (ED50 = 0.205 μmol/kg) and leukocyte infiltration (ED50 = 0.188 μmol/kg) with an efficacy comparable to a high dose of budesonide (1 μmol/kg i.p.). In sum, CHF6001 has the potential to be an effective topical treatment of conditions associated with pulmonary inflammation, including

  13. Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors

    PubMed Central

    2015-01-01

    Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of topoisomerase I/II and HDAC with good antiproliferative and apoptotic activities. This proof-of-concept study also validated the effectiveness of discovering triple topoisomerase I/II and HDAC inhibitors as novel antitumor agents. PMID:25815139

  14. Design of Novel β-Carboline Derivatives with Pendant 5-Bromothienyl and Their Evaluation as Phosphodiesterase-5 Inhibitors

    PubMed Central

    El-Gamil, Dalia S.; Ahmed, Nermin S.; Gary, Bernard D.; Piazza, Gary A.; Engel, Matthias; Hartmann, Rolf W.; Abadi, Ashraf H.

    2016-01-01

    New derivatives with the tetrahydro-β-carboline-imidazolidinedione and tetrahydro-β-carboline-piperazinedione scaffolds and a pendant bromothienyl moiety at C-5/C-6 were synthesized and tested for their ability to inhibit PDE5 in vitro. The following SAR can be concluded: The tetracyclic scaffold is essential for PDE5 inhibition; the ethyl group is the most suitable among the adopted N-substituents on the terminal ring (hydantoin/piperazinedione); the appropriate stereochemistry of C-5/C-6 derived from the aldehyde rather than C-11a/C-12a derived from tryptophan appears crucial for inhibition of PDE5; surprisingly, derivatives with the hydantoin terminal ring are more active than their analogs with the piperazinedione ring; the selectivity versus PDE5 relative to PDE11 with cGMP as a substrate is mainly a function of the substitution and stereochemistry pattern of the external ring, in other words of the interaction with the H-loop residues of the isozymes. Thirteen derivatives showed PDE5 inhibitory activity with IC50 values in the range of 0.16–5.4 μm. Compound 8 was the most potent PDE5 inhibitor and showed selectivity towards PDE5 versus other PDEs, with a selectivity index of 49 towards PDE5 rather than PDE11 with cGMP as the substrate. PMID:23307609

  15. Long-term cognitive dysfunction in the rat following docetaxel treatment is ameliorated by the phosphodiesterase-4 inhibitor, rolipram.

    PubMed

    Callaghan, Charlotte K; O'Mara, Shane M

    2015-09-01

    Clinical studies report evidence of long-term cognitive and other deficits following adjunctive chemotherapy treatment, which is often termed "chemobrain" or "chemo-fog". The neurological bases of these impairments are poorly understood. Here, we hypothesize that systemic chemotherapy treatment causes long-term neurobehavioral deficits, and that these deficits are reversed by manipulation of cAMP by the PDE4 inhibitor, rolipram. Male han Wistar rats were treated with docetaxel (an adjunctive chemotherapeutic agent (1mg/kg i.v.)) or control solution (ethanol/Tween 20/0.9% Saline - 5/5/90) once per week for 4 weeks. They were allowed to recover for 4 weeks, administration of rolipram (0.5mg/kg po) or vehicle (maple syrup) then began and continued daily for 4 weeks. At the end of the treatment regime animals were tested for spatial and recognition memory deficits with the object exploration task and for depressive- and anxiety-like behavior in the forced swim test (FST) and open field exploration. We report docetaxel treatment impaired spatial memory but not object recognition memory, compared to control rats. Docetaxel-treated rats also spent significantly more time immobile than controls in the FST. Chronic rolipram treatment attenuated all of these docetaxel-associated changes, recovering spatial memory and reducing immobility. In conclusion, docetaxel-treated rats exhibit alterations in spatial memory and depressive-like behavior, which are reversed following chronic rolipram administration. These results detect long-term cognitive and mood changes following docetaxel treatment and identify PDE4 inhibition as a target treatment of neuropsychological changes associated with "chemobrain". PMID:25940764

  16. Treatment satisfaction among men with concurrent benign prostatic hyperplasia and erectile dysfunction treated with tadalafil or other phosphodiesterase type-5 inhibitor combinations

    PubMed Central

    Lee, Lulu K; Goren, Amir; Boytsov, Natalie N; Donatucci, Craig F; McVary, Kevin T

    2016-01-01

    Objective Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) frequently co-occur in men aged ≥40, along with lower urinary tract symptoms (LUTS) secondary to BPH. Given little real-world evidence on treatment use or satisfaction with treatment for concurrent BPH/LUTS and/or ED, this study examined medication regimens and differences in satisfaction and health-related quality of life (HRQoL) across regimens among men with concurrent BPH and ED. Methods A cross-sectional study was conducted using an Internet survey of participants recruited through an online panel. Respondents (N=736) included men (aged ≥40) who self-reported a diagnosis of both ED and BPH with prescription treatment in the past 3 months for both conditions. Treatment satisfaction (eg, convenience and ease of planning) and HRQoL (eg, International Prostate Symptom Score, sleep quality) were self-reported. Generalized linear models examined the association of regimen with treatment satisfaction and HRQoL, adjusting for covariates (eg, age and comorbidities). Results Final analyses included participants (N=507) using: tadalafil once-daily monotherapy (22%), tadalafil for ED with an alternate BPH therapy (36%), or another phosphodiesterase type-5 inhibitor (PDE5-I) combination (41%). These groups represented the major categories of treatment regimens found in the sample, excluded participants with ambiguous regimens, and were aligned with current standard of care for BPH and ED. Overall, patients reported moderate levels of BPH and a moderate-to-severe degree of ED. Tadalafil monotherapy patients had higher treatment satisfaction scores and greater reported ease of treatment planning and convenience than PDE5-I combination patients. No significant intergroup differences were found on HRQoL. Conclusion A majority of patients (59%) took tadalafil alone or in combination for BPH/ED treatment. Tadalafil monotherapy patients reported greater treatment satisfaction than patients taking PDE5

  17. High-performance liquid chromatography with diode array detection method for the simultaneous determination of seven selected phosphodiesterase-5 inhibitors and serotonin reuptake inhibitors used as male sexual enhancers.

    PubMed

    Baker, Mostafa M; Belal, Tarek S; Mahrous, Mohamed S; Ahmed, Hytham M; Daabees, Hoda G

    2016-05-01

    This work presents a simple, sensitive and generic high-performance liquid chromatography with diode array detection method for the simultaneous determination of seven drugs prescribed for the treatment of erectile dysfunction and premature ejaculation. Investigated drugs include the phosphodiesterase-5 inhibitors: sildenafil, tadalafil, and vardenafil, in addition to the selective serotonin reuptake inhibitors: dapoxetine, duloxetine, fluoxetine, and paroxetine. The drugs were separated using a Waters C8 column (4.6 × 250 mm, 5 μm) with the mobile phase consisting of phosphate buffer pH 3, acetonitrile and methanol in the ratio 60:33:7. The flow rate was 1.2 mL/min, and quantification was based on measuring peak areas at 225 nm. Peaks were perfectly resolved with retention times 3.3, 3.9, 6.4, 7.5, 9.5, 10.7, and 13.4 min for vardenafil, sildenafil, paroxetine, duloxetine, dapoxetine, fluoxetine, and tadalafil, respectively. The developed method was validated with respect to system suitability, linearity, ranges, accuracy, precision, robustness, and limits of detection and quantification. The proposed method showed good linearity in the ranges 5-500, 2-200, 2-200, 3-300, 1.5-150, 2-200, and 2-200 μg/mL for sildenafil, tadalafil, vardenafil, dapoxetine, duloxetine fluoxetine, and paroxetine, respectively. The limits of detection were 0.18-0.38 μg/mL for the analyzed compounds. The applicability of the proposed method to real life situations was assessed through the analysis of commercial tablets, and satisfactory results were obtained. PMID:26970347

  18. Two Phosphodiesterases from Ustilago Maydis Share Structural and Biochemical Properties with Non-Fungal Phosphodiesterases

    PubMed Central

    Agarwal, Charu; Schultz, David J.; Perlin, Michael H.

    2010-01-01

    The dependence of Protein Kinase A (PKA) activity on cAMP levels is an important facet of the dimorphic switch between budding and filamentous growth as well as for pathogenicity in some fungi. To better understand these processes in the pathogenic fungus Ustilago maydis, we characterized the structure and biochemical functions of two phosphodiesterase (PDE) genes. Phosphodiesterases are enzymes involved in cAMP turnover and thus, contribute to the regulation of the cAMP-PKA signaling pathway. Two predicted homologs of PDEs were identified in the genome of U. maydis and hypothesized to be involved in cAMP turnover, thus regulating activity of the PKA catalytic subunit. Both umpde1 and umpde2 genes contain domains associated with phosphodiesterase activity predicted by InterPro analysis. Biochemical characterization of recombinantly produced UmPde1 (U. maydis Phosphodiesterase I) and UmPde2 demonstrated that both enzymes have phosphodiesterase activity in vitro, yet neither was inhibited by the phosphodiesterase inhibitor IBMX. Moreover, UmPde1 is specific for cAMP, while UmPde2 has broader substrate specificity, utilizing cAMP and cGMP as substrates. In addition, UmPde2 was also found to have nucleotide phosphatase activity that was higher with GMP compared to AMP. These results demonstrate that UmPde1 is a bona fide phosphodiesterase, while UmPde2 has more general activity as a cyclic nucleotide phosphodiesterase and/or GMP/AMP phosphatase. Thus, UmPde1 and UmPde2 likely have important roles in cell morphology and development and share some characteristics with a variety of non-fungal phosphodiesterases. PMID:21687762

  19. Regulation by phosphodiesterase isoenzymes of non-adrenergic non-cholinergic contraction in guinea-pig isolated main bronchus.

    PubMed Central

    Spina, D.; Harrison, S.; Page, C. P.

    1995-01-01

    1. We have investigated the role of phosphodiesterase isoenzymes in modulating electric field stimulation (EFS), substance P and capsaicin-induced contraction of the guinea-pig isolated main bronchus. 2. Non-adrenergic non-cholinergic contractile responses were elicited by EFS (3 Hz, 20 s) in the guinea-pig isolated main bronchus in the presence of the non-selective muscarinic antagonist, atropine (0.1 microM), the non-selective beta-adrenoceptor antagonist, propranolol (1 microM), the neutral endopeptidase inhibitor, thiorphan (10 microM) and the cyclo-oxygenase inhibitor, indomethacin (5 microM). The type III, type III/IV, type IV and type V phosphodiesterase isoenzyme inhibitor, SKF 94836, benzafentrine, Ro-20-1724 and zaprinast respectively, significantly attenuated the contractile response to EFS. The IC50 (95% confidence limits) value for SKF 94836, benzafentrine, Ro-20-1724 and zaprinast was 8.3 microM (0.89-78); 0.7 microM (0.1-4.5); 0.5 microM (0.2-1.2) and 13 microM (2-87) respectively. 3. The phosphodiesterase isoenzyme inhibitors, SKF 94836, Ro-20-1724 and zaprinast, partially attenuated the contractile response to substance P (10 nM). Benzafentrine significantly inhibited the contractile response to substance P, yielding an IC50 value of 1.9 microM (0.9-3.8). 4. The phosphodiesterase isoenzyme inhibitor, Ro-20-1724 (0.1-100 microM) failed to reduce significantly the contractile potency of capsaicin (P > 0.05). In contrast, SKF 94836 (1 microM), benzafentrine (10 microM) and zaprinast (100 microM) significantly reduced the contractile potency of capsaicin (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8564269

  20. EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts

    PubMed Central

    Lal, Bachchu; Goodwin, Courtney R.; Sang, Yingying; Foss, Catherine A.; Cornet, Kathrine; Muzamil, Sameena; Pomper, Martin G.; Kim, Jin; Laterra, John

    2010-01-01

    Receptor tyrosine kinase (RTK) systems, such as hepatocyte growth factor (HGF) and its receptor c-Met, and EGFR, are responsible for the malignant progression of multiple solid tumors. Recent research shows that these RTK systems co-modulate overlapping and dynamically adaptable oncogenic downstream signaling pathways. This paper investigates how EGFRvIII, a constitutively active EGFR deletion mutant, alters tumor growth and signaling responses to RTK inhibition in PTEN-null/HGF+/c-Met+ glioma xenografts. We show that a neutralizing anti-HGF mAb (L2G7) potently inhibits tumor growth and the activation of Akt and MAPK in PTEN-null/HGF+/c-Met+/EGFRvIII−U87 glioma xenografts (U87wt). Isogenic EGFRvIII+ U87 xenografts (U87-EGFRvIII), which grew 5-times more rapidly than U87-wt xenografts, were unresponsive to EGFRvIII inhibition by erlotinib and were only minimally responsive to anti-HGF mAb. EGFRvIII-expression diminished the magnitude of Akt inhibition and completely prevented MAPK inhibition by L2G7. Despite the lack of response to L2G7 or erlotinib as single agents, their combination synergized to produce substantial anti-tumor effects (inhibited tumor cell proliferation, enhanced apoptosis, arrested tumor growth, prolonged animal survival), against subcutaneous and orthotopic U87-EGFRvIII xenografts. The dramatic response to combining HGF:c-Met and EGFRvIII pathway inhibitors in U87-EGFRvIII xenografts occurred in the absence of Akt and MAPK inhibition. These findings show that combining c-Met and EGFRvIII pathway inhibitors can generate potent anti-tumor effects in PTEN-null tumors. They also provide insights into how EGFRvIII and c-Met may alter signaling networks and reveal the potential limitations of certain biochemical biomarkers to predict the efficacy of RTK inhibition in genetically diverse cancers. PMID:19584231

  1. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors.

    PubMed

    Ji, Hongbin; Zhao, Xiaojun; Yuza, Yuki; Shimamura, Takeshi; Li, Danan; Protopopov, Alexei; Jung, Boonim L; McNamara, Kate; Xia, Huili; Glatt, Karen A; Thomas, Roman K; Sasaki, Hidefumi; Horner, James W; Eck, Michael; Mitchell, Albert; Sun, Yangping; Al-Hashem, Ruqayyah; Bronson, Roderick T; Rabindran, Sridhar K; Discafani, Carolyn M; Maher, Elizabeth; Shapiro, Geoffrey I; Meyerson, Matthew; Wong, Kwok-Kin

    2006-05-16

    The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation. PMID:16672372

  2. Modulating the Cyclic Guanosine Monophosphate Substrate Selectivity of the Phosphodiesterase 3 Inhibitors by Pyridine, Pyrido[2,3-d]pyrimidine Derivatives and Their Effects upon the Growth of HT-29 Cancer Cell Line

    PubMed Central

    Abadi, Ashraf Hassan; Hany, Marwa Saeed; Elsharif, Shimaa Awadain; Eissa, Amal Abdel Haleem; Gary, Bernard DeWayne; Tinsley, Heather Nicole; Piazza, Gary Anthony

    2016-01-01

    Analogues with the scaffolds of 3-cyano-4-alkoxyphenyl-6-bromoaryl-2-pyridone and 2-amino-3-cyano-4-alkoxyphenyl-6-bromoarylpyridine were synthesized. Cyclization of the 2-amino derivatives with formic acid and formamide gave the corresponding pyrido[2,3-d]pyrimidin-4(3H)-one and the pyrido[2,3-d]pyrimidin-4-amine derivatives, respectively. Active phosphodiesterase 3 (PDE3) inhibitors were identified from each of the four aforementioned scaffolds. This is the first report that pyrido[2,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4-amine derivatives can inhibit PDE3. The analogues with the pyridone and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds inhibited both cAMP and cyclic guanosine monophosphate (cGMP) hydrolysis by PDE3, while the amine containing scaffolds were more selective for cGMP hydrolysis. This observation may set the base for substrate-selective pharmacological modulation of this important class of drug targets and with less side effects, particularly tachcardia. The dual inhibitors of PDE3 were more potent inhibitor towards the growth of HT-29 cancer cell lines. PMID:23546000

  3. NEW RENIN-INHIBITORS--STABILITY AND ACTIVITY DETERMINATION. PART III.

    PubMed

    Marszałek, Dorota; Goldnik, Anna; Winiecka, Iwona; Jaworski, Paweł; Mazurek, Aleksander P

    2016-01-01

    A series of new four potential renin inhibitors containing pseudodipeptides were synthesized. Stability for all compounds (1-4) in homogenates of liver, kidney, lung and in serum, gastric, intestinal juice and in the presence of α-chymotrypsin was determined. Compound 1 was unstable, compounds 2, 3 were stable, compound 4 was partly unstable, (liver and kidney homogenates, (α-chymotrypsin solution). Inhibitory activity of the compounds was measured in vitro by HPLC determination of lowering concentration of substrate (angiotensinogen) in the presence of renin and the potential renin inhibitor (compounds 1-4). Compound 1, 2, 3 and 4 showed inhibitory activity (1.7 x 10(-6), 9.6 x 10(-7), 1.05 x 10(-9) and 1.31 x 10(-7)M, respectively). PMID:27180425

  4. Highly Potent and Selective Ectonucleotide Pyrophosphatase/Phosphodiesterase I Inhibitors Based on an Adenosine 5′-(α or γ)- Thio-(α,β- or β,γ)-methylenetriphosphate Scaffold

    PubMed Central

    Nadel, Yael; Lecka, Joanna; Gilad, Yocheved; Ben-David, Gal; Förster, Daniel; Reiser, Georg; Kenigsberg, Sarah; Camden, Jean; Weisman, Gary A.; Senderowitz, Hanoch; Sévigny, Jean; Fischer, Bilha

    2015-01-01

    Aberrant nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) activity is associated with chondrocalcinosis, osteoarthritis, and type 2 diabetes. The potential of NPP1 inhibitors as therapeutic agents, and the scarceness of their structure–activity relationship, encouraged us to develop new NPP1 inhibitors. Specifically, we synthesized ATP-α-thio-β,γ- CH2 (1), ATP-α-thio-β,γ-CCl2 (2), ATP-α-CH2-γ-thio (3), and 8-SH-ATP (4) and established their resistance to hydrolysis by NPP1,3 and NTPDase1,2,3,8 (<5% hydrolysis) (NTPDase = ectonucleoside triphosphate diphosphohydrolase). Analogues 1–3 at 100 μM inhibited thymidine 5′-monophosphate p-nitrophenyl ester hydrolysis by NPP1 and NPP3 by >90% and 23–43%, respectively, and only slightly affected (0–40%) hydrolysis of ATP by NTPDase1,2,3,8. Analogue 3 is the most potent NPP1 inhibitor currently known, Ki = 20 nM and IC50 = 0.39 μM. Analogue 2a is a selective NPP1 inhibitor with Ki = 685 nM and IC50 = 0.57 μM. Analogues 1–3 were found mostly to be nonagonists of P2Y1/P2Y2/P2Y11 receptors. Docking analogues 1–3 into the NPP1 model suggested that activity correlates with the number of H-bonds with binding site residues. In conclusion, we propose analogues 2a and 3 as highly promising NPP1 inhibitors. PMID:24846781

  5. Identification of an Iridium(III)-Based Inhibitor of Tumor Necrosis Factor-α.

    PubMed

    Kang, Tian-Shu; Mao, Zhifeng; Ng, Chan-Tat; Wang, Modi; Wang, Wanhe; Wang, Chunming; Lee, Simon Ming-Yuen; Wang, Yitao; Leung, Chung-Hang; Ma, Dik-Lung

    2016-04-28

    The novel iridium(III) complex 1 was verified as a potent inhibitor of the TNF-α-TNFR protein-protein interaction in vitro and in cellulo. The iridium(III) center plays a critical role in organizing the structure of the bioactive metal complex, as the isolated ligands were found to be completely inactive. Both iridium enantiomers inhibited TNF-α-induced NF-κB activity and TNF-α-TNFR binding. 1 represents a promising scaffold for the further development of more potent organometallic TNF-α inhibitors. PMID:27054262

  6. The phosphodiesterase 4 inhibitor roflumilast augments the Th17-promoting capability of dendritic cells by enhancing IL-23 production, and impairs their T cell stimulatory activity due to elevated IL-10.

    PubMed

    Bros, Matthias; Montermann, Evelyn; Cholaszczyńska, Anna; Reske-Kunz, Angelika B

    2016-06-01

    Phosphodiesterase 4 (PDE4) inhibitors serve to prevent degradation of the intracellular second messenger cAMP, resulting in broad anti-inflammatory effects on different cell types including immune cells. Agents that elevate cAMP levels via activation of adenylate cyclase have been shown to imprint a Th17-promoting capacity in dendritic cells (DCs). Therefore, we studied the potential of therapeutically relevant PDE inhibitors to induce a pronounced Th17-skewing capacity in DCs. Here we show that mouse bone marrow-derived (BM-) DCs when treated with the PDE4 inhibitor roflumilast (ROF, trade name: Daxas) in the course of stimulation with LPS (ROF-DCs) evoked elevated IL-17 levels in cocultured allogeneic T cells. In addition, as compared with control settings, levels of IFN-γ remained unaltered, while contents of Th2 cytokines (IL-5, IL-10) were diminished. ROF enhanced expression of the Th17-promoting factor IL-23 in BM-DCs. In line, neutralizing antibodies specific for IL-23 or IL-6 when applied to DC/T cell cocultures partially inhibited the IL17-promoting effect of ROF-DCs. Furthermore, ROF-DCs displayed a markedly diminished allogeneic T cell stimulatory capacity due to enhanced production of IL-10, which was restored upon application of IL-10 specific neutralizing antibody to DC/T cell cocultures. Both the IL-17-inducing and impaired T cell stimulatory capacity of BM-DCs were mimicked by a specific activator of protein kinase A, while stimulation of EPACs (exchange proteins of activated cAMP) did not yield such effects. Taken together, our findings suggest that PDE4 inhibitors aside from their broad overall anti-inflammatory effects may enhance the Th17-polarizing capacity in DCs as an unwanted side effect. PMID:27070502

  7. Identification of HDAC Inhibitors Using a Cell-Based HDAC I/II Assay.

    PubMed

    Hsu, Chia-Wen; Shou, David; Huang, Ruili; Khuc, Thai; Dai, Sheng; Zheng, Wei; Klumpp-Thomas, Carleen; Xia, Menghang

    2016-07-01

    Histone deacetylases (HDACs) are a class of epigenetic enzymes that regulate gene expression by histone deacetylation. Altered HDAC function has been linked to cancer and neurodegenerative diseases, making HDACs popular therapeutic targets. In this study, we describe a screening approach for identification of compounds that inhibit endogenous class I and II HDACs. A homogeneous, luminogenic HDAC I/II assay was optimized in a 1536-well plate format in several human cancer cell lines, including HCT116 and human neural stem cells. The assay confirmed 37 known HDAC inhibitors from two libraries of known epigenetics-active compounds. Using the assay, we identified a group of potential HDAC inhibitors by screening the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection of 2527 small-molecule drugs. The selected compounds showed similar HDAC I/II inhibitory potency and efficacy values in both HCT116 and neural stem cells. Several previously unidentified HDAC inhibitors were further evaluated and profiled for their selectivity against a panel of 10 HDAC I/II isoforms using fluorogenic HDAC biochemical assays. In summary, our results show that several novel HDAC inhibitors, including nafamostat and piceatannol, have been identified using the HDAC I/II cell-based assay, and multiple cell types have been validated for high-throughput screening of large chemical libraries. PMID:26858181

  8. Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors.

    PubMed

    Therrien, Eric; Larouche, Guillaume; Nguyen, Natalie; Rahil, Jubrail; Lemieux, Anne-Marie; Li, Zuomei; Fournel, Marielle; Yan, Theresa P; Landry, Anne-Julie; Lefebvre, Sylvain; Wang, James J; MacBeth, Kyle; Heise, Carla; Nguyen, Aaron; Besterman, Jeffrey M; Déziel, Robert; Wahhab, Amal

    2015-06-15

    A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2. PMID:25971769

  9. Structure elucidation of fungal beauveriolide III, a novel inhibitor of lipid droplet formation in mouse macrophages.

    PubMed

    Namatame, I; Tomoda, H; Tabata, N; Si, S; Omura, S

    1999-01-01

    The structure of fungal beauveriolide III, an inhibitor of lipid droplet formation in mouse macrophages, was elucidated to be cyclo-[(3S,4S)-3-hydroxy-4-methyloctanoyl-L-phenylalanyl-L-alanyl- D-allo-isoleucyl] by spectral analyses and chemical degradation. PMID:10092190

  10. An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy

    PubMed Central

    Bai, Wen-Jun; Li, Hong-Jun; Dai, Yu-Tian; He, Xue-You; Huang, Yi-Ran; Liu, Ji-Hong; Sorsaburu, Sebastian; Ji, Chen; Jin, Jian-Jun; Wang, Xiao-Feng

    2015-01-01

    The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naïve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naïve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe. PMID:25370206

  11. The Effect of a Selective Inhibitor of Phosphodiesterase-9 on Oxidative Stress, Inflammation and Cytotoxicity in Neutrophils from Patients with Sickle Cell Anaemia.

    PubMed

    Barbosa, Maritza Cavalcante; de Jesus Dos Santos, Talyta Ellen; Santos, Thayna Nogueira Dos; Pedrosa, Alano Martins; Elias, Darcielle Bruna Dias; Leal, Luzia Kalyne Almeida Moreira; de Araújo Lopes, Amanda; Sasahara, Greyce Luri; Gonçalves Lemes, Romélia Pinheiro

    2016-04-01

    The aim of the study was to investigate the possible anti-inflammatory and antioxidant effects of BAY 73-6691 on neutrophils from SCA patients. This study included 35 patients with a molecular diagnosis of SCA, whose neutrophils were isolated and treated with BAY 73-6691 at the concentrations 100, 10, 1.0 and 0.1 μg/mL. LDH release and MTT assays were performed to verify cell viability. To evaluate oxidative stress, the following parameters were determined by spectrophotometric assays: NO and malondialdehyde (MDA) levels and activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). As inflammatory markers, myeloperoxidase (MPO) levels were evaluated by colorimetric assay and TNF-α by enzyme immunoassay. The results showed that neutrophils from SCA patients not treated with hydroxyurea (HU) had significantly lower NO levels and catalase and SOD activity, as well as significantly higher MDA, MPO and TNF-α levels when compared with neutrophils from SCA patients treated with HU and neutrophils from control group. Treatment of SCA neutrophils with BAY 73-6691 resulted in 94%, 200% and 168% increase in NOx levels, SOD and catalase activity, respectively. In addition, there was a reduction of approximately 46% and 45% in TNF-α and MPO levels, respectively. In SCAHU neutrophils, there was a 30% and 44% increase in NOx levels and SOD activity, respectively, and a 28% and 37% decrease in TNF-α and MPO levels, respectively. However, these effects were observed at cytotoxic doses only. The results of this study are original and demonstrate that inhibition of phosphodiesterase-9 in neutrophils from SCA patients with BAY 73-6691 was able to increase the NO bioavailability and attenuate oxidative stress and inflammation in neutrophils from patients not treated with HU. PMID:26346295

  12. 7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine, a potent inhibitor of cAMP-specific phosphodiesterase, enhancing nuclear protein binding to the CRE consensus sequence in human tumour cells.

    PubMed

    Wagner, Barbara; Jakobs, Sandra; Habermeyer, Michael; Hippe, Frankie; Cho-Chung, Yoon Sang; Eisenbrand, Gerhard; Marko, Doris

    2002-02-15

    The cAMP-specific phosphodiesterase isoenzyme family PDE4 represents the highest cAMP-hydrolysing activity in many human cancer cell lines including the human large cell lung carcinoma cell line LXFL529L. Treatment of LXFL529L cells with the potent PDE4 inhibitor 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine (DC-TA-46) induces dose-dependent growth inhibition. Cells are arrested in the G(1)-phase of the cell cycle and the induction of apoptosis is observed. In this study, we investigated the effect of DC-TA-46 on downstream elements of the cAMP-pathway. DC-TA-46 mediated inhibition of PDE4 activity in LXFL529L cells resulted in an increase of the intracellular cAMP level and significant induction of the activity of protein kinase A (PKA). The regulatory PKA subunit RIalpha was predominantly expressed in LXFL529L cells. In contrast to effects induced by cAMP analogues like 8-Cl-cAMP, the expression of the regulatory subunits of PKA remained unaffected by DC-TA-46. Treatment of LXFL529L cells with DC-TA-46 enhanced the binding of nuclear proteins to the cAMP-responsive element (CRE) consensus sequence TGACGTCA in a time- and dose-dependent manner, indicating the activation of transcription factors by PKA phosphorylation. PMID:11992633

  13. Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

    PubMed Central

    2015-01-01

    A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. PMID:25815146

  14. Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors.

    PubMed

    Rombouts, Frederik J R; Tresadern, Gary; Buijnsters, Peter; Langlois, Xavier; Tovar, Fulgencio; Steinbrecher, Thomas B; Vanhoof, Greet; Somers, Marijke; Andrés, José-Ignacio; Trabanco, Andrés A

    2015-03-12

    A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. PMID:25815146

  15. Protective effects of BAY 73-6691, a selective inhibitor of phosphodiesterase 9, on amyloid-β peptides-induced oxidative stress in in-vivo and in-vitro models of Alzheimer's disease.

    PubMed

    Li, Jian; Liu, Chun-Na; Wei, Ning; Li, Xi-Dong; Liu, Yuan-Yuan; Yang, Rui; Jia, Yu-Jie

    2016-07-01

    Alzheimer's disease (AD) is accompanied by enhanced oxidative stress and excess free radicals. Phosphodiesterase 9 inhibitors (PDE-9Is) showed memory improving effects in many pharmacological deficit models. However, whether BAY 73-6691 (a selective PDE-9I) may attenuate the oxidative stress during the development of AD is still unclear. For this purpose, primary cultures of SH-SY5Y cells were incubated with 20μM beta-amyloid25-35 (Aβ25-35), followed by exposure to different concentrations (50, 100, 150 and 200μg/ml) of BAY 73-6691. Furthermore, the antioxidant effect of BAY 73-6691 was evaluated in mice subjected to intracerebroventricular injection of Aβ25-35 (day 0) and treatment with BAY 73-6691 by intraperitoneal injection once daily (days 1-10). Our results elucidated that treatment with BAY 73-6691 attenuated the Aβ25-35-induced cytotoxicity and oxidative stress in SH-SY5Y cells. In vivo, BAY 73-6691 protected Aβ25-35-induced oxidative damage in hippocampus, associated with the attenuation of impairments in hippocampal neurons. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. Our study identified a neuroprotective role for BAY 73-6691 against Aβ25-35-induced oxidative stress in vivo and in vitro, harboring therapeutic potential for the treatment of AD by alleviating the impairments in spatial memory and hippocampal neurons. PMID:27071547

  16. Rapid regulation of PDE-2 and PDE-4 cyclic AMP phosphodiesterase activity following ligation of the T cell antigen receptor on thymocytes: analysis using the selective inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) and rolipram.

    PubMed

    Michie, A M; Lobban, M; Müller, T; Harnett, M M; Houslay, M D

    1996-02-01

    The PDE2, cyclic GMP-stimulated, and the PDE4, cyclic AMP-specific enzymes provide the major, detectable cyclic AMP phosphodiesterase activities in murine thymocytes. In the absence of the cyclic GMP, PDE4 activity predominated (approximately 80% total) but in the presence of low (10 microM) cyclic GMP concentrations, PDE2 activity constituted the major PDE activity in thymocytes (approximately 80% total). The PDE4 selective inhibitor rolipram dose-dependently inhibited thymocyte PDE4 activity (IC50 approximately 65 nM). PDE2 was dose-dependently activated (EC50 approximately 1 microM) by cyclic GMP and inhibited by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) (IC50 approximately 4 microM). EHNA was shown to serve as a selective inhibitor of PDE-2 activity as assessed from studies using separated PDE1, PDE2, PDE3 and PDE4 species from hepatocytes as well as human PDE2 and PDE4 enzymes. EHNA completely ablated the ability of cyclic GMP to activate PDE2 activity, whilst having a much smaller inhibitory effect on the unstimulated PDE2 activity. EHNA exhibited normal Michaelian kinetics of inhibition for the cyclic GMP-stimulated PDE2 activity with Hill plots near unity. Apparent negative co-operative effect were seen in the absence of cyclic GMP with Hill coefficients of approximately 0.3 for inhibition of PDE2 activity. Within 5 min of challenge of thymocytes with the lectin phytohaemagglutinin (PHA) there was a transient decrease (approximately 83%) in PDE-4 activity and in PDE2 activity (approximately 40%). Both anti-TCR antibodies also caused an initial reduction in the PDE4 activity which was followed by a sustained and profound increase in activity. In contrast to that observed with PHA, anti-TCR/CD3 antisera had little effect on PDE2 activity. It is suggested that, dependent upon the intracellular concentrations of cyclic GMP, thymocyte cyclic AMP metabolism can be expected to switch from being under the predominant control of PDE4 activity to that determined

  17. Targeting Phosphodiesterases in Anti-platelet Therapy

    PubMed Central

    Rondina, Matthew T.; Weyrich, Andrew S.

    2013-01-01

    There are two primary modes of platelet inhibition: blockade of membrane receptors or neutralization of intracellular pathways. Both means of inhibition have proven benefits in the prevention and resolution of atherothrombotic events. With regard to intracellular inhibition, phosphodiesterases (PDEs) are fundamental for platelet function. Platelets possess several PDEs (PDE2, PDE3 and PDE5) that catalyze the hydrolysis of cyclic adenosine 3′-5′-monophosphate (cAMP) and cyclic guanosine 3′-5′-monophosphate (cGMP), thereby limiting the levels of intracellular nucleotides. PDE inhibitors, such as cilostazol and dipyridamole, dampen platelet function by increasing cAMP and cGMP levels. This review focuses on the roles of PDE inhibitors in modulating platelet function, with particular attention paid to drugs that have anti-platelet clinical indications. PMID:22918733

  18. Advances in targeting cyclic nucleotide phosphodiesterases

    PubMed Central

    Maurice, Donald H.; Ke, Hengming; Ahmad, Faiyaz; Wang, Yousheng; Chung, Jay; Manganiello, Vincent C.

    2014-01-01

    Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants. PMID:24687066

  19. Advances in targeting cyclic nucleotide phosphodiesterases.

    PubMed

    Maurice, Donald H; Ke, Hengming; Ahmad, Faiyaz; Wang, Yousheng; Chung, Jay; Manganiello, Vincent C

    2014-04-01

    Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants. PMID:24687066

  20. A Meta-Analysis of Long- Versus Short-Acting Phosphodiesterase 5 Inhibitors: Comparing Combination Use With α-Blockers and α-Blocker Monotherapy for Lower Urinary Tract Symptoms and Erectile Dysfunction

    PubMed Central

    Kim, Hyun Jung; Bae, Jae Hyun; Kim, Jae Heon; Moon, Du Geon; Cheon, Jun

    2015-01-01

    Purpose: Combination therapy with an α-1-adrenergic blocker and phosphodiesterase type 5 inhibitors (PDE5Is) has shown improvements in lower urinary tract symptoms (LUTS) with negligible side effects. Nonetheless, decisive advantages in symptom improvement were insufficient, and there were no clinical differences between long- or short-acting PDE5Is in combination with combination medication. Methods: To review the studies on α-1-adrenergic blocker monotherapy and combination therapy with long vs. short-acting PDE5Is in their use in LUTS and erectile dysfunction (ED). A search of the MEDLINE, Embase, Cochrane Library, and KoreaMed databases was conducted from 2000 to 2014 using combinations of the relevant terms. Among the 323 relevant references discovered, 10 were selected for meta-analysis. The data showed that 616 men received combination therapy (PDE5Is with α-1-adrenergic blockers) or α-1-adrenergic blocker monotherapy. Results: Meta-analysis of the combination therapy showed it was more effective than α-blockers in improving symptoms, with a mean International Prostrate Symptom Score change difference of –1.93 while those of the long- vs. short-acting PDE5I were –2.12 vs. –1.70. Compared to maximum flow rate (Qmax) value with monotherapy, the Qmax increased more with the combination therapy (mean difference of 0.71) while change values were 0.14 and 1.13 for the long- and short-acting PDE5Is, respectively. Residual urine decreased more with the combination therapy than it did with α-1-adrenergic blocker monotherapy with a mean difference of –7.09 while the mean residual urine change values for long- vs. short-acting PDE5Is were –18.83 vs. –5.93. The International Index of Erectile Function value increased by 3.99, 2.85, and 4.85 following combination therapy, and therapy with long- and short-acting PDE5Is. Conclusions: Our meta-analysis suggests that PDE5Is can significantly improve LUTS in men with benign prostatic hyperplasia

  1. The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting β2-adrenoceptor agonist in preclinical animal species

    PubMed Central

    Salmon, Michael; Tannheimer, Stacey L; Gentzler, Terry T; Cui, Zhi-Hua; Sorensen, Eric A; Hartsough, Kimberly C; Kim, Musong; Purvis, Lafe J; Barrett, Edward G; McDonald, Jacob D; Rudolph, Karin; Doyle-Eisele, Melanie; Kuehl, Philip J; Royer, Christopher M; Baker, William R; Phillips, Gary B; Wright, Clifford D

    2014-01-01

    Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3-[[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting β2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose-dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ≤ 10 μg/kg. GS-5759 was also a potent bronchodilator with an ED50 of 0.09 μg/kg in guinea pigs and 3.4 μg/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS-5759 was dosed as a fine-particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 μg/kg for bronchodilation and ED50 = 4.9 μg/kg for inhibition of LPS-induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS-5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS-5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti-inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device. PMID:25505595

  2. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3)

    PubMed Central

    Edwards, Christopher J; Blanco, Francisco J; Crowley, Jeffrey; Birbara, Charles A; Jaworski, Janusz; Aelion, Jacob; Stevens, Randall M; Vessey, Adele; Zhan, Xiaojiang; Bird, Paul

    2016-01-01

    Objective To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents. Methods Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20 mg twice daily or 30 mg twice daily. The efficacy and safety of apremilast were assessed over 52 weeks. Results At week 16, significantly more patients receiving apremilast 20 mg twice daily (28%) and 30 mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p<0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30 mg twice daily (−0.20) versus placebo (−0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement ≥3%, significantly more apremilast 30 mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection. Conclusions Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52 weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile. Trial registration number NCT01212770. PMID:26792812

  3. Molecular insights into the biosynthesis of guadinomine: a type III secretion system inhibitor.

    PubMed

    Holmes, Tracy C; May, Aaron E; Zaleta-Rivera, Kathia; Ruby, J Graham; Skewes-Cox, Peter; Fischbach, Michael A; DeRisi, Joseph L; Iwatsuki, Masato; Ōmura, Satoshi; Khosla, Chaitan

    2012-10-24

    Guadinomines are a recently discovered family of anti-infective compounds produced by Streptomyces sp. K01-0509 with a novel mode of action. With an IC(50) of 14 nM, guadinomine B is the most potent known inhibitor of the type III secretion system (TTSS) of Gram-negative bacteria. TTSS activity is required for the virulence of many pathogenic Gram-negative bacteria including Escherichia coli , Salmonella spp., Yersinia spp., Chlamydia spp., Vibrio spp., and Pseudomonas spp. The guadinomine (gdn) biosynthetic gene cluster has been cloned and sequenced and includes 26 open reading frames spanning 51.2 kb. It encodes a chimeric multimodular polyketide synthase, a nonribosomal peptide synthetase, along with enzymes responsible for the biosynthesis of the unusual aminomalonyl-acyl carrier protein extender unit and the signature carbamoylated cyclic guanidine. Its identity was established by targeted disruption of the gene cluster as well as by heterologous expression and analysis of key enzymes in the biosynthetic pathway. Identifying the guadinomine gene cluster provides critical insight into the biosynthesis of these scarce but potentially important natural products. PMID:23030602

  4. Identification of Small Molecule Inhibitors of Human As(III) S-Adenosylmethionine Methyltransferase (AS3MT)

    PubMed Central

    2015-01-01

    Arsenic is the most ubiquitous environmental toxin and carcinogen. Long-term exposure to arsenic is associated with human diseases including cancer, cardiovascular disease, and diabetes. Human As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT) methylates As(III) to trivalent mono- and dimethyl species that are more toxic and potentially more carcinogenic than inorganic arsenic. Modulators of hAS3MT activity may be useful for the prevention or treatment of arsenic-related diseases. Using a newly developed high-throughput assay for hAS3MT activity, we identified 10 novel noncompetitive small molecule inhibitors. In silico docking analysis with the crystal structure of an AS3MT orthologue suggests that the inhibitors bind in a cleft between domains that is distant from either the As(III) or SAM binding sites. This suggests the presence of a possible allosteric and regulatory site in the enzyme. These inhibitors may be useful tools for future research in arsenic metabolism and are the starting-point for the development of drugs against hAS3MT. PMID:26577531

  5. Effects of metal ions and disulfide bonds on the activity of phosphodiesterase from Trimeresurus stejnegeri venom.

    PubMed

    Peng, Lili; Xu, Xiaolong; Guo, Mingchun; Yan, Xincheng; Wang, Shasha; Gao, Shang; Zhu, Shanshan

    2013-06-01

    Obviously different from the other known phosphodiesterases, the phosphodiesterase from Trimeresurus stejnegeri venom (TS-PDE) consists of two different chains linked with disulfide bonds and contains both endogenous Cu(2+) and Zn(2+). Cu(2+) and Zn(2+) are important for its phosphodiesterase activity. In this study, the effects of metal ions and small-molecule reductants on its structure and activity have been investigated by polyacrylamide gel electrophoresis, high performance liquid chromatography, fluorescence and electron paramagnetic resonance spectroscopy. The results show that TS-PDE has one class of Zn(2+) binding site and two classes of Cu(2+) binding site, including the high affinity activator sites and the low affinity sites. Cu(2+) ions function as a switch for its phosphodiesterase activity. The catalytic activity of TS-PDE does not have an absolute requirement for Cu(2+) and Zn(2+). Mg(2+), Mn(2+), Ni(2+), Co(2+) and Ca(2+) are all effective for its phosphodiesterase activity. TS-PDE has seven disulfide bonds and ten free cysteine residues. l-Ascorbate inhibits the phosphodiesterase activity of TS-PDE through reduction of the Cu(2+), while dithiothreitol, glutathione and tris(2-carboxyethyl)phosphine inhibit the phosphodiesterase activity of TS-PDE by reducing both the Cu(2+) and disulfide bonds. The catalytic activity of TS-PDE relies on its disulfide bonds and bimetallic cluster. In addition, biologically-relevant reductants, glutathione and l-ascorbate, have been found to be endogenous inhibitors to the phosphodiesterase activity of TS-PDE. PMID:23775423

  6. Phosphodiesterase 7 Inhibition Preserves Dopaminergic Neurons in Cellular and Rodent Models of Parkinson Disease

    PubMed Central

    Morales-Garcia, Jose A.; Redondo, Miriam; Alonso-Gil, Sandra; Gil, Carmen; Perez, Concepción; Martinez, Ana; Santos, Angel; Perez-Castillo, Ana

    2011-01-01

    Background Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions. Methodology/Principal Findings Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. Conclusions/Significance Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease. PMID:21390306

  7. Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes – functional importance of phosphodiesterase 4

    PubMed Central

    Tenor, Hermann; Hedbom, Erik; Häuselmann, Hans-Jörg; Schudt, Christian; Hatzelmann, Armin

    2002-01-01

    We studied whether selective inhibitors of cyclic nucleotide hydrolysing phosphodiesterase (PDE) isoenzymes influence IL-1β-induced nitric oxide (NO) release from human articular chondrocytes. In addition, the pattern of PDE isoenzymes contributing to cyclic nucleotide hydrolysis in human chondrocytes was characterized.Chondrocytes were isolated from human osteoarthritic cartilage and cultured in alginate beads. IL-1β-induced chondrocyte products (nitric oxide and prostaglandin E2) were measured in culture supernatants after 48 h incubation time. PDE activities were assessed in chondrocyte lysates. Inducible nitric oxide synthase (iNOS) and PDE4A-D proteins were detected by immunoblotting.The selective PDE4 inhibitors Piclamilast and Roflumilast partially attenuated IL-1β-induced NO production whereas selective inhibitors of PDE2 (EHNA), PDE3 (Motapizone) or PDE5 (Sildenafil) were inactive. Indomethacin reversed the reduction of IL-1β-induced NO by PDE4 inhibitors. It was shown that autocrine prostaglandin E2 (PGE2) enabled PDE4 inhibitors to reduce IL-1β-induced NO in this experimental setting.Major PDE4 and PDE1 activities were identified in chondrocyte lysates whereas only minor activities of PDE2, 3 and 5 were found. IL-1β and cyclic AMP-mimetics upregulated PDE4 activity and this was associated with an augmentation of PDE4B2 protein.Based on the view that nitric oxide contributes to cartilage degradation in osteoarthritis our study suggests that PDE4 inhibitors may have chondroprotective effects. PMID:11834608

  8. DETERMINATION OF CORROSION INHIBITOR CRITERIA FOR TYPE III/IIIA TANKS DURING SALT DISSOLUTION OPERATIONS SUMMARY DOCUMENT

    SciTech Connect

    Mickalonis, J.; Wiersma, B.; Garcia-Diaz, B.

    2009-10-01

    Dissolution of salt from Type III/IIIA waste tanks at the Savannah River Site may create solutions with inhibitor concentrations below those currently required (0.6M OH{sup -} and 1.1M OH{sup -} + NO{sub 2}{sup -}) per the Corrosion Control Program for high nitrate salt solutions (5.5 to 8.5M NO{sub 3}{sup -}). An experimental program was conducted to evaluate the corrosion susceptibility of grade A537 carbon steel for waste simulants containing 4.5-8.5M NaNO{sub 3} with maximum inhibitor concentrations of 0.6M NaOH and 0.2M NaNO{sub 2}. These maximum inhibitor concentrations used in this program are at a reduced level from those currently required. Current requirements were initially established for the Types I, II and IV tanks made of A285 carbon steel. The experimental program involved corrosion testing to evaluate the pitting and stress corrosion stress corrosion cracking (SCC) susceptibility of the Type III/IIIA waste tank materials. The program was conducted in two phases; the results of the first phase were reported previously (WSRC-STI-2006-00029). In this second phase, the corrosion specimens were modified to represent the 'as-fabricated' condition of the tank wall, and included specimens with mill scale, ground welds and stress-relief heat treatments. The complete description of the corrosion testing and the results are reported herein. The collective corrosion test results for A537 carbon steel in high nitrate waste simulants (4.5 - 8.5M) with the maximum inhibitor concentrations of 0.6M NaOH and 0.2M NaNO{sub 2} were as follows: (1) In long-term non-polarized U-bend testing, heat treatment, similar to the waste tank stress relief regime, reduced the incidence of cracking over the 18-month test period. Vapor space SCC was found to initiate on non-heat treated U-bend coupons. (2) In polarized U-bend testing, cracking occurred on U-bend coupons that had welds prepared similar to those in the waste tanks, i.e. ground and heat treated. (3) In electrochemical

  9. Role of phosphodiesterase 5 in synaptic plasticity and memory

    PubMed Central

    Puzzo, Daniela; Sapienza, Salvatore; Arancio, Ottavio; Palmeri, Agostino

    2008-01-01

    Phosphodiesterases (PDEs) are enzymes that break down the phosphodiesteric bond of the cyclic nucleotides, cAMP and cGMP, second messengers that regulate many biological processes. PDEs participate in the regulation of signal transduction by means of a fine regulation of cyclic nucleotides so that the response to cell stimuli is both specific and activates the correct third messengers. Several PDE inhibitors have been developed and used as therapeutic agents because they increase cyclic nucleotide levels by blocking the PDE function. In particular, sildenafil, an inhibitor of PDE5, has been mainly used in the treatment of erectile dysfunction but is now also utilized against pulmonary hypertension. This review examines the physiological role of PDE5 in synaptic plasticity and memory and the use of PDE5 inhibitors as possible therapeutic agents against disorders of the central nervous system (CNS). PMID:18728748

  10. DETERMINATION OF CORROSION INHIBITOR CRITERIA FOR TYPE III IIIA TANKS DURING SALT DISSOLUTION OPERATIONS

    SciTech Connect

    Wiersma, B

    2008-01-04

    Preparation of high level waste for vitrification involves in part the dissolution of salt cake from the carbon steel storage tanks. The salt crystals composing this cake are high in nitrate concentration with the interstitial liquid being high in hydroxide and nitrite concentration. During the salt dissolution process, a stage is reached in which the inhibitors, hydroxide and nitrite, are insufficient to prevent nitrate stress corrosion cracking (SCC) and fall outside the requirements of the corrosion control program. Additional inhibitors, which are necessary to meet the requirements, may be counterproductive to the efficiency of the process and waste minimization. Corrosion testing was initiated to better characterize the necessary inhibitor concentration for high nitrate waste during salt dissolution processing. A four-phase test program is being conducted: (1) electrochemical characterization, (2) accelerated or polarized U-bend testing, (3) long-term (non-polarized) U-bend testing and (4) vapor space U-bend tests. Electrochemical testing, which included cyclic potentiodynamic polarization (CPP), linear polarization resistance (LPR) and open-circuit potential (OCP) measurements, was performed to identify stress corrosion cracking susceptibility, to characterize pitting resistance and to determine the general corrosion rate. Polarized U-bend tests were utilized to assess the effect of minimum inhibitor concentrations and heat treatment on SCC and to determine test parameters for future long-term U-bend testing. Results from CPP, LPR and OCP tests demonstrated that carbon steel formed a protective oxide film and the potential became electropositive during exposure to the waste at all inhibitor concentrations. The tenacity of this film improved as the inhibitor concentration level was increased and the temperature was decreased. This passive film increased the resistance to localized corrosion significantly. Therefore if any of these inhibitor levels are selected

  11. Efficacy and selectivity of phosphodiesterase-targeted drugs to inhibit photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors*

    PubMed Central

    Zhang, Xiujun; Feng, Qing; Cote, Rick H.

    2005-01-01

    Purpose: Phosphodiesterase (PDE) inhibitors are important therapeutic agents, but their effects on photoreceptor PDE (PDE6) and photoreceptor cells are poorly understood. We characterized the potency and selectivity of various classes of PDE inhibitors on purified rod and cone PDE6 and on intact rod outer segments (ROS). Methods: The inhibition constant (KI) of isozyme-selective PDE inhibitors was determined for purified rod and cone PDE6. Perturbations of cGMP levels in isolated ROS suspensions by PDE inhibitors were quantitated by a cGMP enzyme-linked immunoassay. Results: Most PDE5-selective inhibitors are excellent PDE6 inhibitors. Vardenafil, a potent PDE5 inhibitor (KI = 0.2 nM), is the most potent PDE6 inhibitor tested (KI = 0.7 nM). Zaprinast is the only drug that inhibits PDE6 more potently than PDE5. PDE1-selective inhibitors were equally effective in inhibiting PDE6. In intact ROS, PDE inhibitors elevated cGMP levels but none fully inhibited PDE6. Their potency to elevate cGMP levels in ROS was much lower than their ability to inhibit the purified enzyme. Competition between PDE5/6-selective drugs and the inhibitory γ subunit for the active site of PDE6 is proposed to reduce the effectiveness of drugs at the enzyme active site. Conclusions: Several classes of PDE inhibitors equally well inhibit PDE6 as the PDE family to which they are targeted. In intact ROS, high PDE6 concentrations, binding of the γ subunit to the active site, and calcium feedback mechanisms attenuate the effectiveness of PDE inhibitors to inhibit PDE6 and disrupt the cGMP signaling pathway during visual transduction. PMID:16123402

  12. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  13. Ametoctradin is a potent Qo site inhibitor of the mitochondrial respiration complex III.

    PubMed

    Zhu, Xiaolei; Zhang, Mengmeng; Liu, Jingjing; Ge, Jingming; Yang, Guangfu

    2015-04-01

    Ametoctradin is a new Oomycete-specific fungicide under development by BASF. It is a potent inhibitor of the bc1 complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be a Q(o) site inhibitor of bc1 complex. Subsequently, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5-a]pyrimidine. The calculated binding free energies (ΔG(cal)) of newly synthesized analogues as Qo site inhibitors correlated very well (R(2) = 0.96) with their experimental binding free energies (ΔG(exp)). Two compounds (4a and 4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promising bc1 inhibitor. PMID:25784492

  14. Small molecule inhibitors of the Yersinia type III secretion system impair the development of Chlamydia after entry into host cells

    PubMed Central

    2009-01-01

    Background Chlamydiae are obligate intracellular pathogens that possess a type III secretion system to deliver proteins into the host cell during infection. Small molecule inhibitors of type III secretion in Yersinia, termed INPs (Innate Pharmaceuticals AB) were reported to strongly inhibit Chlamydia growth in epithelial cells. In this study we have analyzed the effect of these drugs on bacterial invasiveness. Results We demonstrate that INPs affect Chlamydia growth in a dose dependent manner after bacterial invasion. The efficiency of C. trachomatis L2 and C. caviae GPIC entry into host cells was not altered in the presence of INPs. In C. caviae, entry appears to proceed normally with recruitment of actin and the small GTPases Rac, Cdc42 and Arf6 to the site of bacterial entry. Conclusion INPs have a strong inhibitory effect on Chlamydia growth. However, bacterial invasion is not altered in the presence of these drugs. In the light of these results, we discuss several hypotheses regarding the mode of action of INPs on type III secretion during the Chlamydia infectious cycle. PMID:19383140

  15. Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 (PDE4) inhibitor rolipram on behavior depend on cyclic AMP-response element binding protein (CREB)-mediated neurogenesis in the hippocampus

    PubMed Central

    Li, Yun-Feng; Huang, Ying; Amsdell, Simon L.; Xiao, Lan; O'Donnell, James M.; Zhang, Han-Ting

    2009-01-01

    Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of cAMP-response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these have not been established. In the present study, chronic administration of rolipram produced antidepressant- and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, three weeks following the end of MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB, with its antidepressant- and anxiolytic-like effects resumed. Overall, the present results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram. PMID:19516250

  16. ZD6474, a Multitargeted Inhibitor for Receptor Tyrosine Kinases, Suppresses Growth of Gliomas Expressing an Epidermal Growth Factor Receptor Mutant, EGFRvIII, in the Brain

    PubMed Central

    Yiin, Jia-Jean; Hu, Bo; Schornack, Paul A.; Sengar, Raghvendra S.; Liu, Kun-wei; Feng, Haizhong; Lieberman, Frank S.; Chiou, Shih-Hwa; Sarkaria, Jann N.; Wiener, Erik C.; Ma, Hsin-I; Cheng, Shi-Yuan

    2010-01-01

    Epidermal growth factor receptor (EGFR) vIII is a mutated EGFR that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors. In this study, we investigate the effect of ZD6474 (ZACTIMA, vandetanib), a dual inhibitor for vascular endothelial growth factor receptor 2 and EGFR on growth and angiogenesis of gliomas expressing EGFRvIII. We used two glioma xenograft models, U87MG cells overexpressing EGFRvIII and short-term cultured primary glioma GBM8 cells with EGFRvIII. ZD6474 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas. Moreover, significant inhibition of EGFRvIII-expressing U87MG and GBM8 gliomas was observed compared with their controls. Magnetic resonance imaging analysis using the apparent diffusion coefficient and three-dimensional T2*weighed measurements validated ZD6474 inhibition on tumor growth and angiogenesis in EGFRvIII-expressing GBM8 gliomas. Mechanistically, ZD6474 shows better inhibition of cell growth and survival of U87MG/EGFRvIII, GBM6, and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3, Akt, and Bcl-XL expression. Albeit in lesser extent, ZD6474 also displays suppressions of U87MG/EGFR and GBM12 cells that overexpress wild-type EGFR. Additionally, ZD6474 inhibits activation of extracellular signal-regulated kinase 1/2 in both types of cells, and expression of a constitutively active phosphoinositide 3-kinases partially rescued ZD6474 inhibition in U87MG/EGFRvIII cells. Taken together, these data show that ZD6474 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII-activated signaling mediators, suggesting a potential application of ZD6474 in treatments for glioblastomas that overexpress EGFRvIII. PMID:20371720

  17. Phosphodiesterase 1A Modulates Cystogenesis in Zebrafish

    PubMed Central

    Ward, Christopher J.; Leightner, Amanda C.; Smith, Jordan L.; Agarwal, Reema; Harris, Peter C.; Torres, Vicente E.

    2014-01-01

    Substantial evidence indicates the importance of elevated cAMP in polycystic kidney disease (PKD). Accumulation of cAMP in cystic tissues may be, in part, caused by enhanced adenylyl cyclase activity, but inhibition of cAMP degradation by phosphodiesterases (PDE) likely has an important role, because cAMP is inactivated much faster than it is synthesized. PDE1 is the only PDE family activated by Ca2+, which is reduced in PKD cells. To assess the contribution of the PDE1A subfamily to renal cyst formation, we examined the expression and function of PDE1A in zebrafish. We identified two splice isoforms with alternative starts corresponding to human PDE1A1 and PDE1A4. Expression of the two isoforms varied in embryos and adult tissues, and both isoforms hydrolyzed cAMP with Ca2+/calmodulin dependence. Depletion of PDE1A in zebrafish embryos using splice- and translation-blocking morpholinos (MOs) caused pronephric cysts, hydrocephalus, and body curvature. Human PDE1A RNA and the PKA inhibitors, H89 and Rp-cAMPS, partially rescued phenotypes of pde1a morphants. Additionally, MO depletion of PDE1A aggravated phenotypes in pkd2 morphants, causing more severe body curvature, and human PDE1A RNA partially rescued pkd2 morphant phenotypes, pronephric cysts, hydrocephalus, and body curvature. Together, these data indicate the integral role of PDE1A and cAMP signaling in renal development and cystogenesis, imply that PDE1A activity is altered downstream of polycystin-2, and suggest that PDE1A is a viable drug target for PKD. PMID:24700876

  18. The xylanase inhibitor TAXI-III counteracts the necrotic activity of a Fusarium graminearum xylanase in vitro and in durum wheat transgenic plants.

    PubMed

    Moscetti, Ilaria; Faoro, Franco; Moro, Stefano; Sabbadin, Davide; Sella, Luca; Favaron, Francesco; D'Ovidio, Renato

    2015-08-01

    The xylanase inhibitor TAXI-III has been proven to delay Fusarium head blight (FHB) symptoms caused by Fusarium graminearum in transgenic durum wheat plants. To elucidate the molecular mechanism underlying the capacity of the TAXI-III transgenic plants to limit FHB symptoms, we treated wheat tissues with the xylanase FGSG_03624, hitherto shown to induce cell death and hydrogen peroxide accumulation. Experiments performed on lemmas of flowering wheat spikes and wheat cell suspension cultures demonstrated that pre-incubation of xylanase FGSG_03624 with TAXI-III significantly decreased cell death. Most interestingly, a reduced cell death relative to control non-transgenic plants was also obtained by treating, with the same xylanase, lemmas of TAXI-III transgenic plants. Molecular modelling studies predicted an interaction between the TAXI-III residue H395 and residues E122 and E214 belonging to the active site of xylanase FGSG_03624. These results provide, for the first time, clear indications in vitro and in planta that a xylanase inhibitor can prevent the necrotic activity of a xylanase, and suggest that the reduced FHB symptoms on transgenic TAXI-III plants may be a result not only of the direct inhibition of xylanase activity secreted by the pathogen, but also of the capacity of TAXI-III to avoid host cell death. PMID:25346411

  19. [Inhibitory Properties of Nitrogen-Containing Adamantane Derivatives with Monoterpenoid Fragments Against Tyrosyl-DNA Phosphodiesterase I].

    PubMed

    Zakharenko, A L; Ponomarev, K U; Suslov, E V; Korchagina, D V; Volcho, K P; Vasil'eva, I A; Salakhutdinov, N F; Lavrik, O I

    2015-01-01

    It was found that compounds combining diazaadamantane and monoterpenoid fragments are potent inhibitors of new structural type of human recombinant DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1). It was demonstrated that the inhibition efficiency depended on the length and flexibility of the aliphatic chain of the substituent. PMID:27125028

  20. Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily

    PubMed Central

    Gandin, Valentina; Ferrarese, Alessandro; Dalla Via, Martina; Marzano, Cristina; Chilin, Adriana; Marzaro, Giovanni

    2015-01-01

    Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi-tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds. PMID:26568452

  1. Targeting Cyclic Nucleotide Phosphodiesterase in the Heart: Therapeutic Implications

    PubMed Central

    Miller, Clint L.

    2010-01-01

    The second messengers, cAMP and cGMP, regulate a number of physiological processes in the myocardium, from acute contraction/relaxation to chronic gene expression and cardiac structural remodeling. Emerging evidence suggests that multiple spatiotemporally distinct pools of cyclic nucleotides can discriminate specific cellular functions from a given cyclic nucleotide-mediated signal. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic AMP and/or cyclic GMP, control the amplitude, duration, and compartmentation of cyclic nucleotide signaling. To date, more than 60 different isoforms have been described and grouped into 11 broad families (PDE1–PDE11) based on differences in their structure, kinetic and regulatory properties, as well as sensitivity to chemical inhibitors. In the heart, PDE isozymes from at least six families have been investigated. Studies using selective PDE inhibitors and/or genetically manipulated animals have demonstrated that individual PDE isozymes play distinct roles in the heart by regulating unique cyclic nucleotide signaling microdomains. Alterations of PDE activity and/or expression have also been observed in various cardiac disease models, which may contribute to disease progression. Several family-selective PDE inhibitors have been used clinically or pre-clinically for the treatment of cardiac or vascular-related diseases. In this review, we will highlight both recent advances and discrepancies relevant to cardiovascular PDE expression, pathophysiological function, and regulation. In particular, we will emphasize how these properties influence current and future development of PDE inhibitors for the treatment of pathological cardiac remodeling and dysfunction. PMID:20632220

  2. Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

    PubMed

    Toka, Okan; Tank, Jens; Schächterle, Carolin; Aydin, Atakan; Maass, Philipp G; Elitok, Saban; Bartels-Klein, Eireen; Hollfinger, Irene; Lindschau, Carsten; Mai, Knut; Boschmann, Michael; Rahn, Gabriele; Movsesian, Matthew A; Müller, Thomas; Doescher, Andrea; Gnoth, Simone; Mühl, Astrid; Toka, Hakan R; Wefeld-Neuenfeld, Yvette; Utz, Wolfgang; Töpper, Agnieszka; Jordan, Jens; Schulz-Menger, Jeanette; Klussmann, Enno; Bähring, Sylvia; Luft, Friedrich C

    2015-10-01

    Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population. PMID:26283042

  3. Angiogenic inhibitors delivered by the type III secretion system of tumor-targeting Salmonella typhimurium safely shrink tumors in mice.

    PubMed

    Shi, Lei; Yu, Bin; Cai, Chun-Hui; Huang, Jian-Dong

    2016-12-01

    Despite of a growing number of bacterial species that apparently exhibit intrinsic tumor-targeting properties, no bacterium is able to inhibit tumor growth completely in the immunocompetent hosts, due to its poor dissemination inside the tumors. Oxygen and inflammatory reaction form two barriers and restrain the spread of the bacteria inside the tumors. Here, we engineered a Salmonella typhimurium strain named ST8 which is safe and has limited ability to spread beyond the anaerobic regions of tumors. When injected systemically to tumor-bearing immunocompetent mice, ST8 accumulated in tumors at levels at least 100-fold greater than parental obligate anaerobic strain ST4. ST8/pSEndo harboring therapeutic plasmids encoding Endostatin fused with a secreted protein SopA could target vasculature at the tumor periphery, can stably maintain and safely deliver a therapeutic vector, release angiogenic inhibitors through a type III secretion system (T3SS) to interfere with the pro-angiogenic action of growth factors in tumors. Mice with murine CT26 colon cancer that had been injected with ST8/pSEndo showed efficient tumor suppression by inducing more severe necrosis and inhibiting blooding vessel density within tumors. Our findings provide a therapeutic platform for indirectly acting therapeutic strategies such as anti-angiogenesis and immune therapy. PMID:27558018

  4. Small-molecule inhibitors suppress the expression of both type III secretion and amylovoran biosynthesis genes in Erwinia amylovora.

    PubMed

    Yang, Fan; Korban, Schuyler S; Pusey, P Lawrence; Elofsson, Michael; Sundin, George W; Zhao, Youfu

    2014-01-01

    The type III secretion system (T3SS) and exopolysaccharide (EPS) amylovoran are two essential pathogenicity factors in Erwinia amylovora, the causal agent of the serious bacterial disease fire blight. In this study, small molecules that inhibit T3SS gene expression in E. amylovora under hrp (hypersensitive response and pathogenicity)-inducing conditions were identified and characterized using green fluorescent protein (GFP) as a reporter. These compounds belong to salicylidene acylhydrazides and also inhibit amylovoran production. Microarray analysis of E. amylovora treated with compounds 3 and 9 identified a total of 588 significantly differentially expressed genes. Among them, 95 and 78 genes were activated and suppressed by both compounds, respectively, when compared with the dimethylsulphoxide (DMSO) control. The expression of the majority of T3SS genes in E. amylovora, including hrpL and the avrRpt2 effector gene, was suppressed by both compounds. Compound 3 also suppressed the expression of amylovoran precursor and biosynthesis genes. However, both compounds induced significantly the expression of glycogen biosynthesis genes and siderophore biosynthesis, regulatory and transport genes. Furthermore, many membrane, lipoprotein and exported protein-encoding genes were also activated by both compounds. Similar expression patterns were observed for compounds 1, 2 and 4. Using crab apple flower as a model, compound 3 was capable of reducing disease development in pistils. These results suggest a common inhibition mechanism shared by salicylidene acylhydrazides and indicate that small-molecule inhibitors that disable T3SS function could be explored to control fire blight disease. PMID:23915008

  5. Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate

    PubMed Central

    Li, Junfeng; Zhang, Xiang; Jin, Hongjun; Fan, Jinda; Flores, Hubert; Perlmutter, Joel S.; Tu, Zhude

    2015-01-01

    A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a–j, 19d–j, 20a–b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [18F]18a–e, [18F]18g, and [18F]20a were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a–d and [18F]20a. Micro-PET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington’s disease and schizophrenia. PMID:26430878

  6. Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

    PubMed Central

    Ahmad, Faiyaz; Murata, Taku; Simizu, Kasumi; Degerman, Eva; Maurice, Donald; Manganiello, Vincent

    2014-01-01

    By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners. PMID:25056711

  7. Synthesis and structure-activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS)

    PubMed Central

    Williams, John D.; Torhan, Matthew C.; Neelagiri, Venu; Brown, Carson; Bowlin, Nicholas O.; Di, Ming; McCarthy, Courtney T.; Aiello, Daniel; Peet, Norton P.; Bowlin, Terry L.; Moir, Donald T.

    2015-01-01

    The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure-activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1 µM. PMID:25638499

  8. Mutations in the Pseudomonas aeruginosa Needle Protein Gene pscF Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System

    PubMed Central

    Bowlin, Nicholas O.; Williams, John D.; Knoten, Claire A.; Torhan, Matthew C.; Tashjian, Tommy F.; Li, Bing; Aiello, Daniel; Mecsas, Joan; Hauser, Alan R.; Peet, Norton P.; Bowlin, Terry L.

    2014-01-01

    The type III secretion system (T3SS) is a clinically important virulence mechanism in Pseudomonas aeruginosa that secretes and translocates effector toxins into host cells, impeding the host's rapid innate immune response to infection. Inhibitors of T3SS may be useful as prophylactic or adjunctive therapeutic agents to augment the activity of antibiotics in P. aeruginosa infections, such as pneumonia and bacteremia. One such inhibitor, the phenoxyacetamide MBX 1641, exhibits very responsive structure-activity relationships, including striking stereoselectivity, in its inhibition of P. aeruginosa T3SS. These features suggest interaction with a specific, but unknown, protein target. Here, we identify the apparent molecular target by isolating inhibitor-resistant mutants and mapping the mutation sites by deep sequencing. Selection and sequencing of four independent mutants resistant to the phenoxyacetamide inhibitor MBX 2359 identified the T3SS gene pscF, encoding the needle apparatus, as the only locus of mutations common to all four strains. Transfer of the wild-type and mutated alleles of pscF, together with its chaperone and cochaperone genes pscE and pscG, to a ΔpscF P. aeruginosa strain demonstrated that each of the single-codon mutations in pscF is necessary and sufficient to provide secretion and translocation that is resistant to a variety of phenoxyacetamide inhibitor analogs but not to T3SS inhibitors with different chemical scaffolds. These results implicate the PscF needle protein as an apparent new molecular target for T3SS inhibitor discovery and suggest that three other chemically distinct T3SS inhibitors interact with one or more different targets or a different region of PscF. PMID:24468789

  9. Fusarium graminearum produces different xylanases causing host cell death that is prevented by the xylanase inhibitors XIP-I and TAXI-III in wheat.

    PubMed

    Tundo, Silvio; Moscetti, Ilaria; Faoro, Franco; Lafond, Mickaël; Giardina, Thierry; Favaron, Francesco; Sella, Luca; D'Ovidio, Renato

    2015-11-01

    To shed light on the role of Xylanase Inhibitors (XIs) during Fusarium graminearum infection, we first demonstrated that three out of four F. graminearum xylanases, in addition to their xylan degrading activity, have also the capacity to cause host cell death both in cell suspensions and wheat spike tissue. Subsequently, we demonstrated that TAXI-III and XIP-I prevented both the enzyme and host cell death activities of F. graminearum xylanases. In particular, we showed that the enzymatic inhibition by TAXI-III and XIP-I was competitive and only FGSG_11487 escaped inhibition. The finding that TAXI-III and XIP-I prevented cell death activity of heat inactivated xylanases and that XIP-I precluded the cell death activity of FGSG_11487 - even if XIP-I does not inhibit its enzyme activity - suggests that the catalytic and the cell death activities are separated features of these xylanases. Finally, the efficacy of TAXI-III or XIP-I to prevent host cell death caused by xylanases was confirmed in transgenic plants expressing separately these inhibitors, suggesting that the XIs could limit F. graminearum infection via direct inhibition of xylanase activity and/or by preventing host cell death. PMID:26475196

  10. Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective.

    PubMed

    Bobin, Pierre; Belacel-Ouari, Milia; Bedioune, Ibrahim; Zhang, Liang; Leroy, Jérôme; Leblais, Véronique; Fischmeister, Rodolphe; Vandecasteele, Grégoire

    2016-01-01

    Cyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby regulating multiple aspects of cardiac and vascular muscle functions. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families that are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP, controlling specific cell functions in response to various neurohormonal stimuli. In the myocardium and vascular smooth muscle, the PDE3 and PDE4 families predominate, degrading cAMP and thereby regulating cardiac excitation-contraction coupling and smooth muscle contractile tone. PDE3 inhibitors are positive inotropes and vasodilators in humans, but their use is limited to acute heart failure and intermittent claudication. PDE5 is particularly important for the degradation of cGMP in vascular smooth muscle, and PDE5 inhibitors are used to treat erectile dysfunction and pulmonary hypertension. There is experimental evidence that these PDEs, as well as other PDE families, including PDE1, PDE2 and PDE9, may play important roles in cardiac diseases, such as hypertrophy and heart failure, as well as several vascular diseases. After a brief presentation of the cyclic nucleotide pathways in cardiac and vascular cells, and the major characteristics of the PDE superfamily, this review will focus on the current use of PDE inhibitors in cardiovascular diseases, and the recent research developments that could lead to better exploitation of the therapeutic potential of these enzymes in the future. PMID:27184830

  11. cAMP phosphodiesterase and activator protein of mammalian cAMP phosphodiesterase from Trypanosoma cruzi.

    PubMed

    Gonçalves, M F; Zingales, B; Colli, W

    1980-04-01

    Epimastigote forms of Trypanosoma cruzi contain a soluble cAMP phosphodiesterase. Optimal activity was found at pH 8.0 and in the presence of 5 mM Mn2+. Other cations were less efficient and did not give rise to an additional stimulation when added in the presence of optimal concentrations of Mn2+. The enzyme is not Ca2+ dependent. The apparent Km of the enzyme for the substrate is 40 microM and no kinetic evidence for the existence of two enzymes has been found. Theophylline and caffein did not inhibit the T. cruzi cAMP phosphodiesterase. The enzyme activity does not change during cell growth suggesting that the fluctuation observed in the levels of cAMP are largely a response to variations in adenylyl cyclase activity. The intracellular concentrations of cAMP ranged between 0.04--0.15 microM. No evidence that the T. cruzi cAMP phosphodiesterase is regulated by an endogenous activator could be found. However, T. cruzi contains a heat-stable, low molecular weight, non-dialysable protein that activates mammalian cAMP phosphodiesterase in the presence of Ca2+. The properties so far studied of such an activator suggest that it might be equivalent to other Ca2+-dependent regulators described in vertebrate and invertebrate species. PMID:6255327

  12. Catalytic mechanism of Escherichia coli ribonuclease III: kinetic and inhibitor evidence for the involvement of two magnesium ions in RNA phosphodiester hydrolysis

    PubMed Central

    Sun, Weimei; Pertzev, Alexandre; Nicholson, Allen W.

    2005-01-01

    Escherichia coli ribonuclease III (RNase III; EC 3.1.24) is a double-stranded(ds)-RNA-specific endonuclease with key roles in diverse RNA maturation and decay pathways. E.coli RNase III is a member of a structurally distinct superfamily that includes Dicer, a central enzyme in the mechanism of RNA interference. E.coli RNase III requires a divalent metal ion for activity, with Mg2+ as the preferred species. However, neither the function(s) nor the number of metal ions involved in catalysis is known. To gain information on metal ion involvement in catalysis, the rate of cleavage of the model substrate R1.1 RNA was determined as a function of Mg2+ concentration. Single-turnover conditions were applied, wherein phosphodiester cleavage was the rate-limiting event. The measured Hill coefficient (nH) is 2.0 ± 0.1, indicative of the involvement of two Mg2+ ions in phosphodiester hydrolysis. It is also shown that 2-hydroxy-4H-isoquinoline-1,3-dione—an inhibitor of ribonucleases that employ two divalent metal ions in their catalytic sites—inhibits E.coli RNase III cleavage of R1.1 RNA. The IC50 for the compound is 14 μM for the Mg2+-supported reaction, and 8 μM for the Mn2+-supported reaction. The compound exhibits noncompetitive inhibitory kinetics, indicating that it does not perturb substrate binding. Neither the O-methylated version of the compound nor the unsubstituted imide inhibit substrate cleavage, which is consistent with a specific interaction of the N-hydroxyimide with two closely positioned divalent metal ions. A preliminary model is presented for functional roles of two divalent metal ions in the RNase III catalytic mechanism. PMID:15699182

  13. Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia.

    PubMed

    Downing, J W; Ramasubramanian, R; Johnson, R F; Minzter, B H; Paschall, R L; Sundell, H W; Engelhardt, B; Lewis, R

    2004-01-01

    The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction

  14. Synthesis of sildenafil analogues from anacardic acid and their phosphodiesterase-5 inhibition.

    PubMed

    Paramashivappa, R; Phani Kumar, P; Subba Rao, P V; Srinivasa Rao, A

    2002-12-18

    Anacardic acid (6-pentadecylsalicylic acid), a major component of cashew nut shell liquid, consists of a heterogeneous mixture of monoenes, dienes, and trienes. The enes mixture of anacardic acid was hydrogenated to a saturated compound. Using saturated anacardic acid as a starting material, analogues of sildenafil [a potent phosphodiesterase-5 (PDE(5)) inhibitor and an orally active drug for the treatment of erectile dysfunction] were synthesized, to observe the effect of the pentadecyl side chain on PDE(5) inhibition. The synthesized compounds were characterized by spectral studies and tested for PDE(5) inhibition, and the results were compared with those obtained with sildenafil. PMID:12475293

  15. Burkholderia pseudomallei Type III Secretion System Cluster 3 ATPase BsaS, a Chemotherapeutic Target for Small-Molecule ATPase Inhibitors

    PubMed Central

    Gong, Lan; Lai, Shu-Chin; Treerat, Puthayalai; Prescott, Mark; Adler, Ben

    2015-01-01

    Melioidosis is an infectious disease of high mortality for humans and other animal species; it is prevalent in tropical regions worldwide. The pathogenesis of melioidosis depends on the ability of its causative agent, the Gram-negative bacterium Burkholderia pseudomallei, to enter and survive in host cells. B. pseudomallei can escape from the phagosome into the cytosol of phagocytic cells where it replicates and acquires actin-mediated motility, avoiding killing by the autophagy-dependent process, LC3 (microtubule-associated protein light chain 3)-associated phagocytosis (LAP). The type III secretion system cluster 3 (TTSS3) facilitates bacterial escape from phagosomes, although the mechanism has not been fully elucidated. Given the recent identification of small-molecule inhibitors of the TTSS ATPase, we sought to determine the potential of the predicted TTSS3 ATPase, encoded by bsaS, as a target for chemotherapeutic treatment of infection. A B. pseudomallei bsaS deletion mutant was generated and used as a control against which to assess the effect of inhibitor treatment. Infection of RAW 264.7 cells with wild-type bacteria and subsequent treatment with the ATPase inhibitor compound 939 resulted in reduced intracellular bacterial survival, reduced escape from phagosomes, and increased colocalization with both LC3 and the lysosomal marker LAMP1 (lysosome-associated membrane protein 1). These changes were similar to those observed for infection of RAW 264.7 cells with the bsaS deletion mutant. We propose that treatment with the ATPase inhibitor compound 939 decreased intracellular bacterial survival through a reduced ability of bacteria to escape from phagosomes and increased killing via LAP. Therefore, small-molecule inhibitors of the TTSS3 ATPase have potential as therapeutic treatments against melioidosis. PMID:25605762

  16. Burkholderia pseudomallei type III secretion system cluster 3 ATPase BsaS, a chemotherapeutic target for small-molecule ATPase inhibitors.

    PubMed

    Gong, Lan; Lai, Shu-Chin; Treerat, Puthayalai; Prescott, Mark; Adler, Ben; Boyce, John D; Devenish, Rodney J

    2015-04-01

    Melioidosis is an infectious disease of high mortality for humans and other animal species; it is prevalent in tropical regions worldwide. The pathogenesis of melioidosis depends on the ability of its causative agent, the Gram-negative bacterium Burkholderia pseudomallei, to enter and survive in host cells. B. pseudomallei can escape from the phagosome into the cytosol of phagocytic cells where it replicates and acquires actin-mediated motility, avoiding killing by the autophagy-dependent process, LC3 (microtubule-associated protein light chain 3)-associated phagocytosis (LAP). The type III secretion system cluster 3 (TTSS3) facilitates bacterial escape from phagosomes, although the mechanism has not been fully elucidated. Given the recent identification of small-molecule inhibitors of the TTSS ATPase, we sought to determine the potential of the predicted TTSS3 ATPase, encoded by bsaS, as a target for chemotherapeutic treatment of infection. A B. pseudomallei bsaS deletion mutant was generated and used as a control against which to assess the effect of inhibitor treatment. Infection of RAW 264.7 cells with wild-type bacteria and subsequent treatment with the ATPase inhibitor compound 939 resulted in reduced intracellular bacterial survival, reduced escape from phagosomes, and increased colocalization with both LC3 and the lysosomal marker LAMP1 (lysosome-associated membrane protein 1). These changes were similar to those observed for infection of RAW 264.7 cells with the bsaS deletion mutant. We propose that treatment with the ATPase inhibitor compound 939 decreased intracellular bacterial survival through a reduced ability of bacteria to escape from phagosomes and increased killing via LAP. Therefore, small-molecule inhibitors of the TTSS3 ATPase have potential as therapeutic treatments against melioidosis. PMID:25605762

  17. Regulation of cAMP by Phosphodiesterases in Erythrocytes

    PubMed Central

    Adderley, Shaquria P.; Sprague, Randy S.; Stephenson, Alan H.; Hanson, Madelyn S.

    2010-01-01

    The erythrocyte, a cell responsible for carrying and delivering oxygen in the body, has often been regarded as simply a vehicle for the circulation of hemoglobin. However, it has become evident that this cell also participates in the regulation of vascular caliber in the microcirculation via release of the potent vasodilator, adenosine triphosphate (ATP). The regulated release of ATP from erythrocytes occurs via a defined signaling pathway and requires increases in cyclic 3’ 5’ adenosine monophosphate (cAMP). It is well recognized that cAMP is a critical second messenger in diverse signaling pathways. In all cells increases in cAMP are localized and regulated by the activity of phosphodiesterases (PDEs). In erythrocytes activation of either β adrenergic receptors (β 2AR) or the prostacyclin receptor (IPR) results in increases in cAMP and ATP release. Receptor-mediated increases in cAMP are tightly regulated by distinct PDEs associated with each signaling pathway as shown by the finding that selective inhibitors of the PDEs localized to each pathway potentiate both increases in cAMP and ATP release. Here we review the profile of PDEs identified in erythrocytes, their association with specific signaling pathways and their role in the regulation of ATP release from these cells. Understanding the contribution of PDEs to the control of ATP release from erythrocytes identifies this cell as a potential target for the development of drugs for the treatment of vascular disease. PMID:20631411

  18. Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Bales, Kelly R.; Plath, Niels; Svenstrup, Niels; Menniti, Frank S.

    Alzheimer's Disease (AD) is a disease of synaptic dysfunction that ultimately proceeds to neuronal death. There is a wealth of evidence that indicates the final common mediator of this neurotoxic process is the formation and actions on synaptotoxic b-amyloid (Aβ). The premise in this review is that synaptic dysfunction may also be an initiating factor in for AD and promote synaptotoxic Aβ formation. This latter hypothesis is consistent with the fact that the most common risk factors for AD, apolipoprotein E (ApoE) allele status, age, education, and fitness, encompass suboptimal synaptic function. Thus, the synaptic dysfunction in AD may be both cause and effect, and remediating synaptic dysfunction in AD may have acute effects on the symptoms present at the initiation of therapy and also slow disease progression. The cyclic nucleotide (cAMP and cGMP) signaling systems are intimately involved in the regulation of synaptic homeostasis. The phosphodiesterases (PDEs) are a superfamily of enzymes that critically regulate spatial and temporal aspects of cyclic nucleotide signaling through metabolic inactivation of cAMP and cGMP. Thus, targeting the PDEs to promote improved synaptic function, or 'synaptic resilience', may be an effective and facile approach to new symptomatic and disease modifying therapies for AD. There continues to be a significant drug discovery effort aimed at discovering PDE inhibitors to treat a variety of neuropsychiatric disorders. Here we review the current status of those efforts as they relate to potential new therapies for AD.

  19. Discovery of plant phenolic compounds that act as type III secretion system inhibitors or inducers of the fire blight pathogen, Erwinia amylovora.

    PubMed

    Khokhani, Devanshi; Zhang, Chengfang; Li, Yan; Wang, Qi; Zeng, Quan; Yamazaki, Akihiro; Hutchins, William; Zhou, Shan-Shan; Chen, Xin; Yang, Ching-Hong

    2013-09-01

    Erwinia amylovora causes a devastating disease called fire blight in rosaceous plants. The type III secretion system (T3SS) is one of the important virulence factors utilized by E. amylovora in order to successfully infect its hosts. By using a green fluorescent protein (GFP) reporter construct combined with a high-throughput flow cytometry assay, a library of phenolic compounds and their derivatives was studied for their ability to alter the expression of the T3SS. Based on the effectiveness of the compounds on the expression of the T3SS pilus, the T3SS inhibitors 4-methoxy-cinnamic acid (TMCA) and benzoic acid (BA) and one T3SS inducer, trans-2-(4-hydroxyphenyl)-ethenylsulfonate (EHPES), were chosen for further study. Both the T3SS inhibitors (TMCA and BA) and the T3SS inducer (EHPES) were found to alter the expression of T3SS through the HrpS-HrpL pathway. Additionally, TMCA altered T3SS expression through the rsmBEa-RsmAEa system. Finally, we found that TMCA and BA weakened the hypersensitive response (HR) in tobacco by suppressing the T3SS of E. amylovora. In our study, we identified phenolic compounds that specifically targeted the T3SS. The T3SS inhibitor may offer an alternative approach to antimicrobial therapy by targeting virulence factors of bacterial pathogens. PMID:23770912

  20. Cross-talk between glucagon- and adenosine-mediated signalling systems in rat hepatocytes: effects on cyclic AMP-phosphodiesterase activity.

    PubMed Central

    Robles-Flores, M; Allende, G; Piña, E; García-Sáinz, J A

    1995-01-01

    The effect of adenosine analogues on glucagon-stimulated cyclic AMP accumulation in rat hepatocytes was explored. N6-Cyclopentyladenosine (CPA), 5'-N-ethylcarboxamidoadenosine and N6-(R-phenylisopropyl)adenosine inhibited in a dose-dependent manner the cyclic AMP accumulation induced by glucagon. This effect seems to be mediated through A1 adenosine receptors. Pertussis toxin completely abolished the effect of CPA on glucagon-stimulated cyclic AMP accumulation in whole cells which suggested that a pertussis-toxin-sensitive G-protein was involved. On the other hand, this action of adenosine analogues on glucagon-induced cyclic AMP accumulation was reverted by the selective low-Km cyclic AMP-phosphodiesterase inhibitor Ro 20-1724. Analysis of cyclic AMP-phosphodiesterase activity in purified hepatocyte plasma membranes showed that glucagon in the presence of GTP inhibited basal PDE activity by 45% and that CPA reverted this inhibition in dose-dependent manner. In membranes derived from pertussis-toxin-treated rats, we observed no inhibition of cyclic AMP-phosphodiesterase activity by glucagon in the absence or presence of CPA. Our results indicate that in hepatocyte plasma membranes, stimulation of adenylate cyclase activity and inhibition of a low-Km cyclic AMP phosphodiesterase activity are co-ordinately regulated by glucagon, and that A1 adenosine receptors can inhibit glucagon-stimulated cyclic AMP accumulation by blocking glucagon's effect on phosphodiesterase activity. Images Figure 2 PMID:8554517

  1. Inhibition of Phosphodiesterase-4 during Pneumococcal Pneumonia Reduces Inflammation and Lung Injury in Mice.

    PubMed

    Tavares, Luciana P; Garcia, Cristiana C; Vago, Juliana P; Queiroz-Junior, Celso M; Galvão, Izabela; David, Bruna A; Rachid, Milene A; Silva, Patrícia M R; Russo, Remo C; Teixeira, Mauro M; Sousa, Lirlândia P

    2016-07-01

    Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, treated with ROL in a prophylactic or therapeutic schedule in combination, or not, with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed, and ex vivo phagocytosis assays were performed. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases. PMID:26677751

  2. In Silico Screening for Novel Inhibitors of DNA Polymerase III Alpha Subunit of Mycobacterium tuberculosis (MtbDnaE2, H37Rv)

    PubMed Central

    Jadaun, Alka; Sudhakar D, Raja; Subbarao, N.; Dixit, Aparna

    2015-01-01

    Tuberculosis, a pandemic disease is caused by Mycobacterium tuberculosis (Mtb). DNA polymerase III encoded by DnaE2 of Mtb is specifically required for its survival in vivo, and hence can be considered to be a potential drug target. Amino acid sequence analysis of the MtbDnaE2 and its human counterpart does not show any significant similarity. Therefore, a 3D model of the MtbDnaE2 was generated using Modeller 9v10 with the template structure of E. Coli DNA polymerase III alpha subunit (2HNH_A). The generated models were validated using a number of programmes such as RAMPAGE/PROCHECK, VERIFY_3D, and ProSA. MtbDnaE2 has few conserved residues and four conserved domains similar to that present in DNA polymerase III of E. coli. In silico screening was performed with bioactive anti-tuberculosis compounds and 6-AU (a known inhibitor of DNA polymerase III of Bacillus subtilis) and its analogues against the modeled MtbDnaE2 structure. Docking was performed using GOLD v5.2 software which resulted in the identification of top ten compounds with high GOLD fitness scores and binding affinity (X-Score). To further evaluate the efficacy of these compounds, in silico ADMET analysis was performed using MedChem Designer v3. Given their high binding affinity to the targeted MtbDnaE2, which is essential for DNA replication in the Mtb and good ADMET properties, these compounds are promising candidates for further evaluation and development as anti-tubercular agents. PMID:25811866

  3. Psychiatric aspects of phosphodiesterases: An overview

    PubMed Central

    Murthy, Vasantmeghna S.; Mangot, Ajish G.

    2015-01-01

    Phosphodiesterases (PDE) are exciting new targets in medical sciences. These enzymes are some of the key mediators of cellular functions in the body and hence are attractive sites for drug-induced modulations. With the finding that Tofisopam, a new anxiolytic, inhibits PDEs, the authors were inspired to look into the role of PDE and drugs acting on them in psychiatry. Hence, the review was undertaken. We found several research materials available highlighting the role of PDE in cellular functions and the possible newer etiological mechanisms of neuropsychiatric illnesses such as schizophrenia, depression/anxiety disorders, and cognitive dysfunction involving PDEs. We also found that there are many molecules acting on PDEs, which have the potential to alter the way we treat mental illnesses today. This article is intended to provide an in-depth look at these enzymes so that more cost-effective therapeutic molecules may be synthesized and marketed in India for managing mental illnesses. PMID:26729948

  4. Nitric Oxide Signaling in Pseudomonas aeruginosa Biofilms Mediates Phosphodiesterase Activity, Decreased Cyclic Di-GMP Levels, and Enhanced Dispersal▿ †

    PubMed Central

    Barraud, Nicolas; Schleheck, David; Klebensberger, Janosch; Webb, Jeremy S.; Hassett, Daniel J.; Rice, Scott A.; Kjelleberg, Staffan

    2009-01-01

    Bacteria in biofilms often undergo active dispersal events and revert to a free-swimming, planktonic state to complete the biofilm life cycle. The signaling molecule nitric oxide (NO) was previously found to trigger biofilm dispersal in the opportunistic pathogen Pseudomonas aeruginosa at low, nontoxic concentrations (N. Barraud, D. J. Hassett, S. H. Hwang, S. A. Rice, S. Kjelleberg, and J. S. Webb, J. Bacteriol. 188:7344-7353, 2006). NO was further shown to increase cell motility and susceptibility to antimicrobials. Recently, numerous studies revealed that increased degradation of the secondary messenger cyclic di-GMP (c-di-GMP) by specific phosphodiesterases (PDEs) triggers a planktonic mode of growth in eubacteria. In this study, the potential link between NO and c-di-GMP signaling was investigated by performing (i) PDE inhibitor studies, (ii) enzymatic assays to measure PDE activity, and (iii) direct quantification of intracellular c-di-GMP levels. The results suggest a role for c-di-GMP signaling in triggering the biofilm dispersal event induced by NO, as dispersal requires PDE activity and addition of NO stimulates PDE and induces the concomitant decrease in intracellular c-di-GMP levels in P. aeruginosa. Furthermore, gene expression studies indicated global responses to low, nontoxic levels of NO in P. aeruginosa biofilms, including upregulation of genes involved in motility and energy metabolism and downregulation of adhesins and virulence factors. Finally, site-directed mutagenesis of candidate genes and physiological characterization of the corresponding mutant strains uncovered that the chemotaxis transducer BdlA is involved in the biofilm dispersal response induced by NO. PMID:19801410

  5. DETERMINATION OF CORROSION INHIBITOR CRITERIA FOR TYPE III/IIIA TANKS DURING SALT DISSOLUTION OPERATIONS INTERIM REPORT

    SciTech Connect

    Counts, K; Bruce Wiersma, B; John Mickalonis, J

    2007-12-31

    Preparation of high level waste for vitrification involves in part the dissolution of salt cake from the carbon steel storage tanks. During dissolution, a point is reached in which the corrosion inhibitors, hydroxide and nitrite, are diluted below established guidelines, and nitrate stress corrosion cracking (SCC) is possible. Because the addition of inhibitors may be counterproductive to process efficiency and waste minimization, corrosion testing was initiated to revisit and possibly revise the guidelines for inhibitor limits. The bases for the work summarized in this status report are results from previously-completed phases of study. In the first two phases of study, several reduced-inhibitor levels were tested in HLW simulants with nitrate concentrations ranging from 4.5 M to 8.5 M. The first two phases of work determined, among other things, the reduced-inhibitor levels and solution chemistries in which heat-treated and non-heat-treated A537 carbon steel is susceptible to SCC, crevice corrosion, and pitting. The work covered in this current task both builds on and verifies the conclusions of the previous work. The current work involves testing of low levels of inhibitors in HLW simulants with 5.5 M to 8.5 M nitrate concentrations. Stressed U-bend specimens, both polarized and non-polarized, were tested. Non-polarized U-bend testing is ongoing, with the U-bends currently in test for 100 days. The purpose of the testing is to determine SCC susceptibility in the vapor space (VS) and liquid air interface (LAI) regions of the HLW tanks under conditions expected during salt dissolution, and also to verify previous accelerated testing. The simulated wastes being tested have nitrate concentrations of 5.5 M and 8.5 M and inhibitor levels of 0.01 M/0.01 M hydroxide/nitrite and 0.1 M/ 0.1 M hydroxide/nitrite. The open circuit potential measurements being monitored and the corrosion morphology of the U-bends are in agreement with results and observations of previous

  6. ABCD of the phosphodiesterase family: interaction and differential activity in COPD

    PubMed Central

    Halpin, David MG

    2008-01-01

    Phosphodiesterases (PDEs) are important enzymes that hydrolyze the cyclic nucleotides adenosine 3′5′-cyclic monophosphate (cAMP) and guanosine 3′5′-cyclic mono-phosphate (cGMP) to their inactive 5′ monophosphates. They are highly conserved across species and as well as their role in signal termination, they also have a vital role in intracellular localization of cyclic nucleotide signaling and integration of the cyclic nucleotide pathways with other signaling pathways. Because of their pivotal role in intracellular signaling, they are now of considerable interest as therapeutic targets in a wide variety diseases, including COPD where PDE inhibitors may have bronchodilator, anti-inflammatory and pulmonary vasodilator actions. This review examines the diversity and cellular localization of the isoforms of PDE, the known and speculative relevance of this to the treatment of COPD, and the range of PDE inhibitors in development together with a discussion of their possible role in treating COPD. PMID:19281073

  7. Upregulation of Phosphodiesterase type 5 in the Hyperplastic Prostate

    PubMed Central

    Zhang, Wenhao; Zang, Ning; Jiang, Yaoming; Chen, Ping; Wang, Xinghuan; Zhang, Xinhua

    2015-01-01

    Both erectile dysfunction (ED) and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) are common in the aging male. Numerous clinical trials have demonstrated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5-Is) for treating LUTS/BPH with/without ED. However, the influence of BPH on prostatic PDE5 expression has never been studied. A testosterone-induced rat model of BPH was developed and human hyperplastic prostate specimens were harvested during cystoprostatectomy. PDE5, nNOS, eNOS and α1-adrenoreceptor subtypes (α1aARs, α1bARs and α1dARs) were determined with real-time RT-PCR for rat tissues whilst PDE5 and α1-adrenoreceptor subtypes were determined in human samples. PDE5 was further analyzed with Western-blot and histological examination. Serum testosterone was measured with ELISA. The rat BPH model was validated as having a significantly enlarged prostate. PDE5 localized mainly in fibromuscular stroma in prostate. Our data showed a significant and previously undocumented upregulation of PDE5 in both rat and human BPH, along with increased expression of nNOS and α1dARs for rat tissues and α1aARs for human BPH. The upregulation of PDE5 in the hyperplastic prostate could explain the mechanism and contribute to the high effectiveness of PDE5-Is for treating LUTS/BPH. Fibromuscular stroma could be the main target for PDE5-Is within prostate. PMID:26657792

  8. Traumatic Brain Injury Upregulates Phosphodiesterase Expression in the Hippocampus

    PubMed Central

    Wilson, Nicole M.; Titus, David J.; Oliva, Anthony A.; Furones, Concepcion; Atkins, Coleen M.

    2016-01-01

    Traumatic brain injury (TBI) results in significant impairments in hippocampal synaptic plasticity. A molecule critically involved in hippocampal synaptic plasticity, 3′,5′-cyclic adenosine monophosphate, is downregulated in the hippocampus after TBI, but the mechanism that underlies this decrease is unknown. To address this question, we determined whether phosphodiesterase (PDE) expression in the hippocampus is altered by TBI. Young adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. Animals were analyzed by western blotting for changes in PDE expression levels in the hippocampus. We found that PDE1A levels were significantly increased at 30 min, 1 h and 6 h after TBI. PDE4B2 and 4D2 were also significantly increased at 1, 6, and 24 h after TBI. Additionally, phosphorylation of PDE4A was significantly increased at 6 and 24 h after TBI. No significant changes were observed in levels of PDE1B, 1C, 3A, 8A, or 8B between 30 min to 7 days after TBI. To determine the spatial profile of these increases, we used immunohistochemistry and flow cytometry at 24 h after TBI. PDE1A and phospho-PDE4A localized to neuronal cell bodies. PDE4B2 was expressed in neuronal dendrites, microglia and infiltrating CD11b+ immune cells. PDE4D was predominantly found in microglia and infiltrating CD11b+ immune cells. To determine if inhibition of PDE4 would improve hippocampal synaptic plasticity deficits after TBI, we treated hippocampal slices with rolipram, a pan-PDE4 inhibitor. Rolipram partially rescued the depression in basal synaptic transmission and converted a decaying form of long-term potentiation (LTP) into long-lasting LTP. Overall, these results identify several possible PDE targets for reducing hippocampal synaptic plasticity deficits and improving cognitive function acutely after TBI. PMID:26903822

  9. Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling

    PubMed Central

    Tian, Xia; Vroom, Christina; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Bieniek, Ewa; Grimminger, Friedrich; Seeger, Werner; Schermuly, Ralph Theo; Pullamsetti, Soni Savai

    2011-01-01

    Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%–50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH. PMID:21494592

  10. Phosphodiesterase 10A upregulation contributes to pulmonary vascular remodeling.

    PubMed

    Tian, Xia; Vroom, Christina; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Bieniek, Ewa; Grimminger, Friedrich; Seeger, Werner; Schermuly, Ralph Theo; Pullamsetti, Soni Savai

    2011-01-01

    Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%-50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH. PMID:21494592