Epoxide hydrolase inhibitor

It was recently reported that. >97% of BaP 4,5-epoxide metabolically formed from the metabolism of BaP in a reconstituted enzyme system containing purified cytochrome P-450c (P-448) is the 4S,5R enantiomer (24). The epoxide was determined by formation, separation and quantification of the diastereomeric trans-addition products of glutathione. Recently a BaP 4,5-epoxide was isolated from a metabolite mixture obtained from the metabolism of BaP by liver microsomes from 3-methylcholanthrene-treated Sprague-Dawley rats in the presence of the epoxide hydrolase inhibitor 3,3,3-trichloropropylene oxide, and was found to contain a 4S,5R/4R,5S enantiomer ratio of 94 6 (Chiu et. al., unpublished results). However, the content of the 4S,5R enantiomer was <60% when liver microsomes from untreated and phenobarbital-treated rats were used as the enzyme sources. Because BaP 4R,5S-epoxide is also hydrated predominantly to 4R,5R-dihydro-... 

In a study in which liver microsomes, prepared from male Wistar rats (200-250 g), were incubated with 5 x 10 mol/L2,3-dibromopH]propan-l-olandanNADPH-gene-rating system, covalent binding to protein was determined. Addition of the epoxide hydrolase inhibitor l,l,l-trichloropropene-2,3-epoxide led to an increase in the proteinbinding rate of 2,3-dibromopropan-l-ol (Soderlund etal., 1981). 

Another example, this one involving epoxide hydrolase inhibitors, is shown in Figure 9.26. Here, only 21% of the para-flnoro Compound 16d was left after 1 h incubation with HLMs,... 

Figure 9.26 Left Epoxide hydrolase inhibitors." Right CCR5 receptor antagonists. ...

Flwang, S.H., et al. Orally bioavailable potent soluble epoxide hydrolase inhibitors. J. Med. Chem. 2007, 50, 3825-3840. 

Aminoheterocycle bioisosteric approaches to amide groupings are exemplified in a report on soluble epoxide hydrolase inhibitors [5j. The replacement of the amide grouping in 1 by adoption of the tethering strategy of linking the carbonyl to adjacent side chains or benzene rings produced 2 (Figure 3.2). 

Mayer, R.J., Booth-Genthe, C.L., and CaUahan, J.F. (2013) In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. 

A specific example of prudent hit-to-lead design is illustrated in the development of soluble epoxide hydrolase inhibitors by Tanaka et al. [16]. By placing more emphasis on ligand efficiency of hits rather than the better absolute potency of larger and more lipophilic hits, they explored the SAR of the cyclopropyl amide shown in Figure 17.5. While the hit compound has only 0.5 micromolar activity, it has quite good ligand efficiency and is amenable to rapid... 

Figure 17.5 An example of selecting and expanding SAR around a soluble epoxide hydrolase Inhibitor hit compound (top) containing a core with a high ligand efficiency. Although It had weaker potency (565 nM), other more potent hits ( 10nM, structures undisclosed) were more lipophilic and not as...

Tanaka, D., Tsuda, Y., Shiyama, T., Nishimura, T., Chiyo, N., Tominaga, Y., Sawada, N., Mimoto, T., and Kusunose, N. (2011) A practical use of ligand efficiency indices out of the fragment-based approach ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors. Journal of Medicinal Chemistry, 54, 851-857. 

Hydroxy amides and keto amides as a primary pharmacophore in soluble epoxide hydrolase inhibitors... 

Scheme 17.21 Synthesis of epoxide hydrolase inhibitor via copper bromide catalysed cross dehydrogenative coupling of aldehydes and...

Morisseau C, Hammock BD. Epoxide hydrolases mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol 2005 45 311-333. 

The overall reaction catalyzed by epoxide hydrolases is the addition of a H20 molecule to an epoxide. Alkene oxides, thus, yield diols (Fig. 10.5), whereas arene oxides yield dihydrodiols (cf. Fig. 10.8). In earlier studies, it had been postulated that epoxide hydrolases act by enhancing the nucleo-philicity of a H20 molecule and directing it to attack an epoxide, as pictured in Fig. 10.5, a [59] [60], Further evidence such as the lack of incorporation of 180 from H2180 into the substrate, the isolation of an ester intermediate, and the effects of group-selective reagents and carefully designed inhibitors led to a more-elaborate model [59][61 - 67]. As pictured in Fig. 10.5,b, nucleophilic attack of the substrate is mediated by a carboxylate group in the catalytic site to form an ester intermediate. In a second step, an activated H20... 

C. Morisseau, G. Du, J. W. Newman, B. D. Hammock, Mechanism of Mammalian Soluble Epoxide Hydrolase by Chalcone Oxide Derivatives , Arch. Biochem. Biophys. 1998, 356, 214 - 228 C. Morisseau, M. H. Goodrow, D. Dowdy, J. Zheng, J. F. Greene, J. R. Sanborn, B. D. Hammock, Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases , Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8849 - 8854. 

It has been proposed that metabolic activation of diphenylhydantoin may be responsible for the teratogenicity. After the administration of radioactively labeled diphenylhydantoin to pregnant mice, radioactive drug or a metabolite was found to be covalently bound to protein in the embryo. It was shown that both the teratogenicity and embryolethality of diphenylhydantoin could be increased by using an inhibitor of epoxide hydrolase (see chap. 4), trichloropropene oxide. Similarly, the covalent binding of radiolabeled diphenylhydantoin to protein was also increased by this treatment. 

A number of inhibitors of this enzyme are known. They include epoxides that are hydrolyzed by the enzymes, such as trichloropropene oxide, metal ions such as Hg2+, Zn2+, and Cd2+ and 2-bromo-4 -acetophenone, a potent inhibitor that binds to imidazole nitrogen atoms. Microsomal epoxide hydrolase can be induced by compounds such asphenobarbital, Arochlor 1254,2(3)-t-butyl-4-hydroxyanisole (BHA), and 3,5-di-f-butyl-hydroxytoluene (BHT). Many microsomal epoxide hydrolase inducers are inducers also of CYP and produce a general proliferation of the endoplasmic reticulum. Induction does, however, involve an increase in the mRNA specific for the hydrolase. 

Drug interactions involving AEDs are shown in Table 52-5. Phenobarbital, phoiytom, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate gjucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzjrme systems and displaces some drugs from plasma albumin. Felbamate and topiramate can act as inducers with some isoforms and inhibitors with others. 

Methyl esters prepared from undecylenic acid and containing an episulfide group were tested as inhibitors of JH III epoxide hydrolase activity to evaluate its biological role in insects <2005MI140>. 

Recently, sterically differently substituted epoxides, such as reactive metabolites of the pesticides vinclozolin, rotenone, and phenothrin, were investigated in terms of their ability to inhibit epoxide hydrolase. Mono-and di-substituted oxiranes were good substrates and strong noncompetitive inhibitors of hepatic epoxide hydrolase, whereas tri-substituted epoxides were virtually inactive in this regard (Cova et al 1986). Obviously, selective inhibition of epoxide hydrolase by epoxide metabolites could interfere with the natural protection of the organism against other toxic epoxides. 

Clinically significant interactions can be caused by inhibitors of epoxide hydrolase, such as valpromide and valnoc-tamide, which increase the serum concentrations of the active metabolite carbamazepine-10,ll-epoxide. 

Valpromide is a more potent inhibitor than valproate of carbamazepine epoxide hydrolase in vitro (129) and in six healthy volunteers it caused a marked rise in carbamazepine-10,ll-epoxide, prolonging the half-life of carbamazepine-10,ll-epoxide from 6.4 to 21 hours and reducing its clearance three-fold, suggesting that valpromide inhibits epoxide hydrolase in the liver in vivo as well as in vitro, despite the fact that it is rapidly converted in vivo to valproate (130). 

In healthy subjects valnoctamide 200 mg tds for 8 days prolonged the half-life of carbamazepine-10,ll-epoxide from 7 to 20 hours and reduced its oral clearance fourfold, suggesting that valnoctamide, like its isomer valpromide, is a potent inhibitor of carbamazepine epoxide hydrolase (130). 

Roe, R., Kallapur, V., Linderman, R. J. and Viviani, F. (2005) Organic synthesis and bioassay of novel inhibitors of JH III epoxide hydrolase activity from fifth stadium cabbage loopers, Trichoplusia ni. Pestic. Biochem. Physiol., 83, 140-154. 

Valproic acid is an enzyme inhibitor that can inhibit specific cytochrome P450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in the clearance of phenobarbital and potential toxicity if the dose of phenobarbital is not reduced. Valproic acid may increase concentrations of 10,11-carbamazepine epoxide without affecting concentrations of the parent drug via inhibition of epoxide hydrolase. Valproic acid is also a potent inhibitor of lamotrigine, via inhibition of UGT enzymes, and can result in a doubling of the half-life of lamotrigine. ... 

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