14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) Surrogates: Carboxylate Modifications | Zendy

John R. Falck | Zendy; Sreenivasulu Reddy Koduru | Zendy; Seetaram Mohapatra | Zendy; R Manne | Zendy; Raju Atcha | Zendy; Vijaya L. Manthati | Zendy; Jorge H. Capdevila | Zendy; Sarah Christian | Zendy; John D. Imig | Zendy; William B. Campbell | Zendy

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14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) Surrogates: Carboxylate Modifications

Author(s) -

John R. Falck,

Sreenivasulu Reddy Koduru,

Seetaram Mohapatra,

R Manne,

Raju Atcha,

Vijaya L. Manthati,

Jorge H. Capdevila,

Sarah Christian,

John D. Imig,

William B. Campbell

Publication year - 2014

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm500262m

Subject(s) - chemistry , epoxide hydrolase 2 , in vivo , carboxylate , tetrazole , eicosanoid , epoxide , bioisostere , epoxide hydrolase , stereochemistry , prodrug , in vitro , chemical synthesis , biochemistry , combinatorial chemistry , enzyme , microsome , arachidonic acid , microbiology and biotechnology , biology , catalysis

The cytochrome P450 eicosanoid 14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a powerful endogenous autacoid that has been ascribed an impressive array of physiologic functions including regulation of blood pressure. Because 14,15-EET is chemically and metabolically labile, structurally related surrogates containing epoxide bioisosteres were introduced and have become useful in vitro pharmacologic tools but are not suitable for in vivo applications. A new generation of EET mimics incorporating modifications to the carboxylate were prepared and evaluated for vasorelaxation and inhibition of soluble epoxide hydrolase (sEH). Tetrazole 19 (ED50 0.18 μM) and oxadiazole-5-thione 25 (ED50 0.36 μM) were 12- and 6-fold more potent, respectively, than 14,15-EET as vasorelaxants; on the other hand, their ability to block sEH differed substantially, i.e., 11 vs >500 nM. These data will expedite the development of potent and specific in vivo drug candidates.

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