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

13 Citations (Scopus)

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 - 2014

Fingerprint

Epoxide Hydrolases
Acids
Autacoids
Oxadiazoles
Thiones
Eicosanoids
Epoxy Compounds
Vasodilator Agents
Vasodilation
Cytochrome P-450 Enzyme System
Blood Pressure
Pharmaceutical Preparations
14,15-epoxy-5,8,11-eicosatrienoic acid
1H-tetrazole
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Falck, J. R., Koduru, S. R., Mohapatra, S., Manne, R., Atcha, R., Manthati, V. L., ... 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

14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates : Carboxylate modifications. / Falck, J R; Koduru, Sreenivasulu Reddy; Mohapatra, Seetaram; Manne, Rajkumar; Atcha, Raju; Manthati, Vijaya L.; Capdevila, Jorge H.; Christian, Sarah; Imig, John D.; Campbell, William B.

In: Journal of Medicinal Chemistry, Vol. 57, No. 16, 2014, p. 6965-6972.

Research output: Contribution to journalArticle

Falck, JR, Koduru, SR, Mohapatra, S, Manne, R, Atcha, R, Manthati, VL, Capdevila, JH, Christian, S, Imig, JD & Campbell, WB 2014, '14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates: Carboxylate modifications', Journal of Medicinal Chemistry, vol. 57, no. 16, pp. 6965-6972. https://doi.org/10.1021/jm500262m
Falck, J R ; Koduru, Sreenivasulu Reddy ; Mohapatra, Seetaram ; Manne, Rajkumar ; Atcha, Raju ; Manthati, Vijaya L. ; Capdevila, Jorge H. ; Christian, Sarah ; Imig, John D. ; Campbell, William B. / 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates : Carboxylate modifications. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 16. pp. 6965-6972.
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