Design and discovery of soluble epoxide hydrolase inhibitors for the treatment of cardiovascular diseases

Expert Opinion on Drug Discovery

Volumn 9, Issue 3, 2014, Pages 229-243

  Duflot, Thomas ^a,b   Roche, Clothilde ^b   Lamoureux, Fabien ^a   Guerrot, Dominique ^a,b   Bellien, Jeremy ^a,b  

^a ROUEN UNIVERSITY HOSPITAL   (France)

^b UNIVERSITY OF ROUEN   (France)

Author keywords

Cardiovascular diseases; Endothelium; Enzymatic inhibitory drugs; Epoxyeicosatrienoic acids; Genetic polymorphisms; Soluble epoxide hydrolase

Indexed keywords

4 SUBSTITUTED BENZOXAZOLONE; APOPTOSIS INHIBITOR; ARACHIDONIC ACID; CHALCONE OXIDE; CYTOCHROME P450; EPOXIDE HYDROLASE; EPOXYICOSATRIENOIC ACID; HYDROLASE INHIBITOR; SOLUBLE EPOXIDE HYDROLASE INHIBITOR; SULFOXIDE; UNCLASSIFIED DRUG; UREA DERIVATIVE;

3' UNTRANSLATED REGION; AMINO ACID SUBSTITUTION; ANGIOGENESIS; BLOOD CLOT LYSIS; CARDIOVASCULAR DISEASE; DRUG DESIGN; DRUG SAFETY; ENDOTHELIAL DYSFUNCTION; ENDOTHELIUM CELL; ENZYME ACTIVITY; ENZYME STRUCTURE; ENZYME SYNTHESIS; EPOXIDATION; GENE EXPRESSION; HUMAN; HYPERPOLARIZATION; METABOLIC DISORDER; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; VASCULAR RESISTANCE; VASODILATATION;

ANIMALS; CARDIOVASCULAR DISEASES; DRUG DISCOVERY; EICOSANOIDS; EPOXIDE HYDROLASES; HUMANS; METABOLIC DISEASES;

EID: 84896737382     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2014.881354     Document Type: Review

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86. Lee CR, Pretorius M, Schuck RN, et al. Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans. Hypertension 2011;57:116-22. This clinical study shows that polymorphisms of EPHX2 affecting sEH activity modify endothelium-dependent vasomotor responses.
87. Burdon KP, Lehtinen AB, Langefeld CD, et al. Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study. Diab Vasc Dis Res 2008;5:128-34
88. Ohtoshi K, Kaneto H, Node K, et al. Association of soluble epoxide hydrolase gene polymorphism with insulin resistance in type 2 diabetic patients. Biochem Biophys Res Commun 2005;331:347-50
89. Sato K, Emi M, Ezura Y, et al. Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intrafamilial association study in an eight-generation hyperlipidemic kindred. J Hum Genet 2004;49:29-34
90. Lee SH, Lee J, Cha R, et al. Genetic variations in soluble epoxide hydrolase and graft function in kidney transplantation. Transplant Proc 2008;40:1353-6
91. Harris TR, Hammock BD. Soluble epoxide hydrolase: Gene structure, expression and deletion. Gene 2013;526:61-74
92. Gschwendtner A, Ripke S, Freilinger T, et al. Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with an increased risk of ischemic stroke in white Europeans. Stroke 2008;39:1593-6
93. Kim I-H, Morisseau C, Watanabe T, Hammock BD. Design, synthesis, and biological activity of 1,3-disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase of increased water solubility. J Med Chem 2004;47:2110-22.. This study describes the structure activity relationship of 1,3-disubsitued urea derivatives.
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95. Dietze EC, Kuwano E, Casas J, Hammock BD. Inhibition of cytosolic epoxide hydrolase by trans-3-phenylglycidols. Biochem Pharmacol 1991;42:1163-75
96. Morisseau C, Du G, Newman JW, Hammock BD. Mechanism of mammalian soluble epoxide hydrolase inhibition by chalcone oxide derivatives. Arch Biochem Biophys 1998;356:214-28
97. Kim I-H, Heirtzler FR, Morisseau C, et al. Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility. J Med Chem 2005;48:3621-9.. The study describes the improvement of water solubility of amide-based inhibitors of sEH.
98. Morisseau C, Goodrow MH, Newman JW, et al. Structural refinement of inhibitors of urea-based soluble epoxide hydrolases. Biochem Pharmacol 2002;63:1599-608
99. Watanabe T, Morisseau C, Newman JW, Hammock BD. In vitro metabolism of the mammalian soluble epoxide hydrolase inhibitor, 1-cyclohexyl-3-dodecyl-urea. Drug Metab Dispos 2003;31:846-53
100. Imig JD, Zhao X, Zaharis CZ, et al. An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension. Hypertension 2005;46:975-81. This is the first oral administration of the sEH inhibitor AUDA, with blood pressure-lowering properties.
101. Liu J-Y, Lin Y-P, Qiu H, et al. Substituted phenyl groups improve the pharmacokinetic profile and antiinflammatory effect of urea-based soluble epoxide hydrolase inhibitors in murine models. Eur J Pharm Sci 2013;48:619-27
102. Argiriadi MA, Morisseau C, Goodrow MH, et al. Binding of alkylurea inhibitors to epoxide hydrolase implicates active site tyrosines in substrate activation. J Biol Chem 2000;275:15265-70
103. Tang L, Ma W-H, Ma Y-L, et al. Synthesis and biological activity of 4-substituted benzoxazolone derivatives as a new class of sEH inhibitors with high anti-inflammatory activity in vivo. Bioorg Med Chem Lett 2013;23:2380-3
104. Morisseau C, Pakhomova S, Hwang SH, et al. Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides. Bioorg Med Chem Lett 2013;23:3818-21
105. Schmelzer KR, Kubala L, Newman JW, et al. Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc Natl Acad Sci USA 2005;102:9772-7
106. Fakhr IM, Radwan MA, el-Batran S, et al. Synthesis and pharmacological evaluation of 2-substituted benzo[b] thiophenes as anti-inflammatory and analgesic agents. Eur J Med Chem 2009;44:1718-25
107. Loch D, Hoey A, Morisseau C, et al. Prevention of hypertension in DOCA-salt rats by an inhibitor of soluble epoxide hydrolase. Cell Biochem Biophys 2007;47:87-98
108. Motoki A, Merkel MJ, Packwood WH, et al. Soluble epoxide hydrolase inhibition and gene deletion are protective against myocardial ischemia-reperfusion injury in vivo. Am J Physiol Heart Circ Physiol 2008;295:H2128-34
109. Chaudhary KR, Abukhashim M, Hwang SH, et al. Inhibition of soluble epoxide hydrolase by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid is protective against ischemia-reperfusion injury. J Cardiovasc Pharmacol 2010;55:67-73
110. Li N, Liu J-Y, Timofeyev V, et al. Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: Insight gained using metabolomic approaches. J Mol Cell Cardiol 2009;47:835-45
111. Merabet N, Bellien J, Glevarec E, et al. Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure. J Mol Cell Cardiol 2012;52:660-6. This is the first report of a beneficial effect of a sEH inhibitor in the treatment of left ventricular hypertrophy and dysfunction in established ischaemic heart failure.
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