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

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• 作者：John R. Falck ; Sreenivasulu Reddy Koduru ; Seetaram Mohapatra ; Rajkumar Manne ; Raju Atcha ; Vijaya L. Manthati ; Jorge H. Capdevila ; Sarah Christian ; John D. Imig ; William B. Campbell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 28, 2014
• 年：2014
• 卷：57
• 期：16
• 页码：6965-6972
• 全文大小：372K
• ISSN：1520-4804

文摘

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 渭M) and oxadiazole-5-thione 25 (ED₅₀ 0.36 渭M) 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.