14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates: Carboxylate modifications

J 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

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6965-6972
Number of pages8
JournalJournal of Medicinal Chemistry
Volume57
Issue number16
DOIs
StatePublished - Aug 28 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of '14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates: Carboxylate modifications'. Together they form a unique fingerprint.

  • Cite this

    Falck, J. R., Koduru, S. R., Mohapatra, S., Manne, R., Atcha, R., Manthati, V. L., Capdevila, J. H., Christian, S., Imig, J. D., & Campbell, W. B. (2014). 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates: Carboxylate modifications. Journal of Medicinal Chemistry, 57(16), 6965-6972. https://doi.org/10.1021/jm500262m