Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the inflammatory process of mammals. It is an epoxide hydrolase and an aminopeptidase of the M1 family of the MA clan of Zn-metallopeptidases. We have solved the crystal structure of LTA4H in complex with ...

. This was the position in which the Vanbrugh found itself when violinist, Elizabeth Charleson, left to pursue a career

A summary of the discovery and advancement of inhibitors of fatty acid amide hydrolase (FAAH) is presented. PMID:21764305

Inhibitors of the soluble epoxide hydrolase (sEH) are provided that incorporate multiple pharmacophores and are useful in the treatment of diseases.

The present invention relates to inhibitors of fatty acid hydrolase. More particularly, the invention relates to inhibitors of fatty acid hydrolase employing a heterocyclic pharmacophore. One aspect of the invention is directed to an inhibitor of fatty ac...

We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein?protein interaction surfaces for fragment binding. We ...

Leukotriene A4 hydrolase (LTA4H), an enzyme involved in the conversion of LTA4 to LTB4, is an emerging and important anti-inflammatory target. This study demonstrates the development of quantitative pharmacophore hypothesis and Bayesian model and their applications in identification of potential human LTA4H (hLTA4H) ...

... BLOOD SERUM, ENZYME INHIBITORS), SEX HORMONES, PEPTIDE HYDROLASES, BIOCHEMISTRY, PLASMIN, TRYPSIN, TESTOSTERONE ...

Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout ...

Benzothiophene piperazine and piperidine urea inhibitors of fatty acid amide hydrolase (FAAH inhibitor Fatty acid amide hydrolase Urea Activity-based protein profiling Covalent inhibitor a b s t r a c urea FAAH inhibitors is described. These compounds inhibit FAAH by ...

Several P450 enzymes localized in the endoplasmic reticulum and thought to be involved primarily in xenobiotic metabolism, including mouse and rat CYP1A1 and mouse CYP1A2, have also been found to translocate to mitochondria. We report here that the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces enzymatically active CYP1A4/1A5, the ...

... well pipettor, we screened 528 natural product extractsfor ... INHIBITORS, DRUGS, NEUROTRANSMITTERS, SELECTION, PEPTIDE HYDROLASES ...

... Descriptors : *ANTICOAGULANTS, *PEPTIDES, SYNTHESIS(CHEMISTRY), ENZYME INHIBITORS, PEPTIDE HYDROLASES, SERINE, AMINO ...

Patterns of scissile bond twisting have been found in crystal structures of glycoside hydrolases (GHs) that are complexed with substrates and inhibitors. To estimate the increased potential energy in the substrates that results from this twisting, we have plotted torsion angles for the scissile bond...

The microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism of xenobiotics such as polyaromatic toxicants. Additionally, polymorphism studies have underlined a potential role of this enzyme in relation to a number of diseases, such as emphysema, spontaneous abortion, eclampsia ...

Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor-inflammatory effects of aspirin or MK886, which was evidenced by the observations that co-administration ...

The metabolism of arachidonic acid by the cyclooxygenase (COX) or lipoxygenase (LO) pathways generates eicosanoids that have been implicated in the pathogenesis of a variety of human diseases, including cancer. In this study, we examined the expression and significance of components within the 5-LO pathway in human neuroblastoma, an embryonal tumor of the sympathetic nervous system. High ...

The epoxide hydrolases (EHs) are enzymes present in all living organisms, which transform epoxide containing lipids by the addition of water. In plants and animals, many of these lipid substrates have potent biologically activities, such as host defenses, control of development, regulation of inflammation and blood pressure. Thus the EHs have important and diverse biological ...

Neutrophils represent a prominent source of pathology in an array of persistent pulmonary diseases. A recent article published in Science describes a novel anti-inflammatory pathway that degrades the neutrophil chemoattractant Pro-Gly-Pro (PGP) to limit neutrophilic inflammation of the lung. Degradation of PGP was mediated through the action of leukotriene ...

Effective inhibitors of S-adenosylhomocysteine hydrolase hold promise towards becoming useful therapeutic agents. Since most efforts have focused on the development of nucleoside analog inhibitors, issues regarding bioavailability and selectivity have been major challenges. Considering the marine sponge metabolite ilimaquinone was ...

Combination of drugs for multiple targets has been a standard treatment in treating various diseases. A single chemical entity that acts upon multiple targets is emerging nowadays because of their predictable pharmacokinetic and pharmacodynamic properties. We have employed a computer-aided methodology combining molecular docking and pharmacophore filtering to identify chemical compounds that can ...

and amide-based inhibitors of the juvenile hormone epoxide hydrolase of the tobacco hornworm (Manduca sexta 2002 Abstract A new class of inhibitors of juvenile hormone epoxide hydrolase (JHEH) of Manduca sexta; Manduca sexta; Metabolism; Inhibitors; Kinetics; Structure activity relationships ...

Hypertension and type II diabetes are co-morbid diseases that lead to the development of nephropathy. Soluble epoxide hydrolase (sEH) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects ...

Steven R. Goldberg Background: Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of...

,3,5,7-adamantane tetracarboxylate) [4b]. These are mainly obtained via hydrothermal methods, while complex 1

production by C. nicoti- anae. However, change of the carbon or nitrogen source in CM slightly influenced

The leukotoxins [9(10)-and 12(13)-EpOME] are produced by activated inflammatory leukocytes such as neutrophils. High EpOME levels are observed in disorders such as acute respiratory distress syndrome and in patients with extensive burns.Although the physiological significance of the EpOMEs remains poorly understood,in some systems, the EpOMEs act as a protoxin,with their corresponding epoxide ...

The leukotoxins [9(10)- and 12(13)-EpOME] are produced by activated inflammatory leukocytes such as neutrophils. High EpOME levels are observed in disorders such as acute respiratory distress syndrome and in patients with extensive burns. Although the physiological significance of the EpOMEs remains poorly understood, in some systems, the EpOMEs act as a protoxin, with their corresponding epoxide ...

The soluble epoxide hydrolase (sEH) plays a significant role in the biosynthesis of inflammation mediators as well as xenobiotic transformations. Herein, we report the discovery of substituted ureas and carbamates as potent inhibitors of sEH. Some of these selective, competitive tightbinding inhibitors with nanomolar Ki values ...

Administration of BAS 100, a novel mechanism-based CYP3A4 inhibitor isolated from grapefruit juice, resulted in a 2.1-fold increase in erlotinib exposure following oral administration to wild-type and humanised CYP3A4 transgenic mice. This study illustrates the potential of BAS 100 to increase ...

The pioneering work of Gerry Brooks on cyclodiene insecticides led to the discovery of a class of enzymes known as epoxide hydrolases. The results from four decades of work confirm Brooks' first observations that the microsomal epoxide hydrolase is important in foreign compound metabolism. Brooks and associates went on to be the first to carry out a ...

The synthesis and structure�activity relationships (SAR) of a series of benzothiophene piperazine and piperidine urea FAAH inhibitors is described. These compounds inhibit FAAH by covalently modifying the enzyme�s active site serine nucleophile. Activity-based protein profiling (ABPP) revealed that these urea inhibitors were completely selective for ...

Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these ...

Serine hydrolases are a diverse enzyme class representing ?1% of all human proteins. The biological functions of most serine hydrolases remain poorly characterized owing to a lack of selective inhibitors to probe their activity in living systems. Here we show that a substantial number of serine hydrolases can be ...

An epoxide hydrolase from Rhodococcus erythropolis DCL14 catalyzes the hydrolysis of limonene-1,2-epoxide to limonene-1,2-diol. The enzyme is induced when R. erythropolis is grown on monoterpenes, reflecting its role in the limonene degradation pathway of this microorganism. Limonene-1,2-epoxide hydrolase was purified to homogeneity. It is a monomeric ...

Furanocoumarins (FCs) are a class of aromatic compounds in grapefruit that inhibit human intestinal cytochrome P450 3A4 (CYP3A4). Since fungi metabolize polycyclic aromatic hydrocarbons, we hypothesized that certain fungi might also metabolize FCs into forms that may be inactive as CYP3A4 ...

Soluble Epoxide Hydrolase Inhibition Protects the Kidney from Hypertension-Induced Damage XUEYING hypertension in- duced renal damage. Chronic administration of the specific SEH inhibitor 1-cyclohexyl-3-dodecylurea (CDU, 3 mg/d) for 10 d lowered BP in angiotensin hypertensive rats. The contri- bution of renal

, unlike most serine hydrolases, there were two serines instead of the typical serine-histidine- aspartic involving a serine-serine-lysine triad. Serine 241 is the nucleophile binding to anandamide and inhibitors-labeled fluorophosphonate that reacts with the broad family of serine hydrolases including FAAH in tissue homoge- nates

to be intra- cellular homo-hexameric cysteine proteases with a papain- like catalytic triad. The enzyme, the human enzyme is not as efficiently inhibited by the cysteine protease inhibitors tested as is the yeast). A bleomycin-inactivating enzyme dis- covered in mice hydrolyzed the carboxyamide bond of the -aminoalanine

The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet f...

This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3-amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.11.2). Some of these novel non-peptidic compounds are potent, ...

Arachidonoyl ethanolamide (anandamide) is an endogenous amide of arachidonic acid and an important signaling mediator of the endocannabinoid system. Given its numerous roles in maintaining normal physiological function and modulating pathophysiological responses throughout the body, the endocannabinoid system is an important pharmacological target amenable to manipulation directly by cannabinoid ...

Arachidonoyl ethanolamide (anandamide) is an endogenous amide of arachidonic acid and an important signaling mediator of the endocannabinoid system. Given its numerous roles in maintaining normal physiological function and modulating pathophysiological responses throughout the body, the endocannabinoid system is an important pharmacological target amenable to manipulation directly by cannabinoid ...

Substituted urea compounds are well-known as potent inhibitors of juvenile hormone epoxide hydrolase (JHEH) of the tobacco hornworm Manduca sexta. Docking simulations of 47 derivatives inside JHEH were performed to gain insight into the structural characteristics of these complexes. The obtained orientations show a strong similitude with the observed in ...

Juvenile hormone (JH) undergoes metabolic degradation by two major pathways involving JH esterase and JH epoxide hydrolase (EH). While considerable effort has been focussed on the study of JH esterase and the development of inhibitors for this enzyme, much less has been reported on the study of JH-EH. In this work, the asymmetric synthesis of two classes ...

Using electrochemical detection, 3-deazaadenosine, a proximal inhibitor of methylation via the inhibition of S-adenosylhomocysteine hydrolase, perturbed the metabolism of catecholamines in the adrenals of rats. In adrenals of rats treated with 3-deazaaden...

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

The present invention provides compounds having the formula: (I); Also provided are pro-drug compounds of the formula: (II); The invention also provides pharmaceutical compositions containing the above compounds, methods of using the above compounds as ph...

The present invention provides compounds having the formula: wherein A is a nitrogen-, oxygen-, or sulfur-linked aryl, alkyl, cyclic, or heterocyclic group, the group being further substituted with an electron contributing moiety; B is hydrogen, or a halo...

The present invention provides compounds having the formula: wherein A is chosen from a nitrogen-, oxygen-, or sulfur-linked aryl, alkyl, cyclic, or heterocyclic group; both B and C are hydrogen, or either B or C is a halogen, amino, or thiol group and th...

) is primarily because they are potent inhibitors 872 lipases, and haloalkane dehalogenase. The active site). The structure of an additional enzyme, haloalkane dehalogenase, which displays struc- tural similarity to ACh

... of the selective JHE inhibitor OTFP to termite homogenates enabled assay of JHEH. Thin layer analysis of ... that metabolites of juvenile hormone III by termite homogenates were juvenile hormone III diol ...

Retrorsine (RTS) and monocrotaline (MCT) cause severe toxicities via P450-mediated metabolic activation. The screening of mechanism-based inhibitors showed RTS inactivated 3A4 in the presence of NADPH. Unlike RTS, MCT failed to inhibit P450 3A4 and other enzymes tested. Further studies showed ...

Depression is genetically determined and inflammation has been implicated. Women are twice as likely to develop depression as men. Whether genetic variants involved in inflammation play a role in the sex difference in depression is unclear. We examined the association, separately in men and women, ...

of existing or proposed inhibitors are used as the descriptors of chemical structure and properties all quantum chemical data (19)). Since molecules described by quantum mechanics have finite electronPrediction of Inhibitor Binding Free Energies by Quantum Neural Networks. Nucleoside Analogues

An exo-?-xylosidase mutant with glycosynthase activity was created to aid in the synthesis of xylanase substrates and inhibitors. Simple monosaccharides were easily elaborated into di-, tri- and tetrasaccharides by using this enzyme. Some products proved to be surprisingly potent inhibitors of xylanases from glycoside hydrolase ...

Frozen rat liver microsomes and rough endoplasmic reticulum were irradiated with high energy electrons. The surviving enzymatic activity of acyl-CoA:cholesterol acyltransferase and activity for esterification of 25-hydroxycholesterol decreased as a simple exponential function of radiation exposure, leading to a target size of 170-180 kDa. The loss of acyl-CoA hydrolase ...

Fatty acid amide hydrolase (FAAH) is responsible for hydrolysis of endocannabinoid, anandamide (AEA), and N-acyl ethanolamines such as palmitoylethanolamine (PEA) and N-oleoylethanolamide (OEA). Genetic deletion or pharmacological inactivation of FAAH shows site-specific elevation of AEA that plays a role in the modulation of pain and other neurodegenerative disorders. The ...

S-Adenosylhomocysteine hydrolase activity decreased in vitro time-dependently in liver homogenates obtained from rats treated in vivo with erythro-9-(2-hydroxynon-3-yl)adenine, a potent inhibitor of adenosine deaminase. The inhibitor in itself had no effect on the stability of the hydrolase. The inactivation of ...

Epoxide hydrolases are essential for the processing of epoxide-containing compounds in detoxification or metabolism. The classic epoxide hydrolases have an ?/? hydrolase fold and act via a two-step reaction mechanism including an enzyme�substrate intermediate. We report here the structure of the limonene-1,2-epoxide ...

We investigated N-adamantyl-N?-phenyl urea derivatives as simple sEH inhibitors. Salicylate ester derivatives have high inhibitory activities against human sEH, while the free benzoic acids are less active. The methyl salicylate derivative is a potent sEH inhibitor, which also has high metabolic and chemical stabilities; suggesting that such ...

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB[subscript 1]-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain. Using a ...