14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres

Influence upon vascular relaxation and soluble epoxide hydrolase inhibition

J R Falck, Ravinder Kodela, Rajkumar Manne, Krishnam Raju Atcha, Narender Puli, Narsimhaswamy Dubasi, Vijay L. Manthati, Jorge H. Capdevila, Xiu Yu Yi, Daniel H. Goldman, Christophe Morisseau, Bruce D. Hammock, William B. Campbell

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

All-cis-14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a labile, vasodilatory eicosanoid generated from arachidonic acid by cytochrome P450 epoxygenases. A series of robust, partially saturated analogues containing epoxide bioisosteres were synthesized and evaluated for relaxation of precontracted bovine coronary artery rings and for in vitro inhibition of soluble epoxide hydrolase (sEH). Depending upon the bioisostere and its position along the carbon chain, varying levels of vascular relaxation and/or sEH inhibition were observed. For example, oxamide 16 and N-iPr-amide 20 were comparable (ED50 1.7 μM) to 14,15-EET as vasorelaxants but were approximately 10-35 times less potent as sEH inhibitors (IC50 59 and 19 μM, respectively); unsubstituted urea 12 showed useful activity in both assays (ED50 3.5 μM, IC50 16 nM). These data reveal differential structural parameters for the two pharmacophores that could assist the development of potent and specific in vivo drug candidates.

Original languageEnglish (US)
Pages (from-to)5069-5075
Number of pages7
JournalJournal of Medicinal Chemistry
Volume52
Issue number16
DOIs
StatePublished - Aug 27 2009

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Epoxide Hydrolases
Epoxy Compounds
Blood Vessels
Inhibitory Concentration 50
Acids
Eicosanoids
Vasodilator Agents
Arachidonic Acid
Amides
Cytochrome P-450 Enzyme System
Urea
Coronary Vessels
Carbon
Pharmaceutical Preparations
14,15-epoxy-5,8,11-eicosatrienoic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres : Influence upon vascular relaxation and soluble epoxide hydrolase inhibition. / Falck, J R; Kodela, Ravinder; Manne, Rajkumar; Atcha, Krishnam Raju; Puli, Narender; Dubasi, Narsimhaswamy; Manthati, Vijay L.; Capdevila, Jorge H.; Yi, Xiu Yu; Goldman, Daniel H.; Morisseau, Christophe; Hammock, Bruce D.; Campbell, William B.

In: Journal of Medicinal Chemistry, Vol. 52, No. 16, 27.08.2009, p. 5069-5075.

Research output: Contribution to journalArticle

Falck, JR, Kodela, R, Manne, R, Atcha, KR, Puli, N, Dubasi, N, Manthati, VL, Capdevila, JH, Yi, XY, Goldman, DH, Morisseau, C, Hammock, BD & Campbell, WB 2009, '14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres: Influence upon vascular relaxation and soluble epoxide hydrolase inhibition', Journal of Medicinal Chemistry, vol. 52, no. 16, pp. 5069-5075. https://doi.org/10.1021/jm900634w
Falck, J R ; Kodela, Ravinder ; Manne, Rajkumar ; Atcha, Krishnam Raju ; Puli, Narender ; Dubasi, Narsimhaswamy ; Manthati, Vijay L. ; Capdevila, Jorge H. ; Yi, Xiu Yu ; Goldman, Daniel H. ; Morisseau, Christophe ; Hammock, Bruce D. ; Campbell, William B. / 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres : Influence upon vascular relaxation and soluble epoxide hydrolase inhibition. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 16. pp. 5069-5075.
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abstract = "All-cis-14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a labile, vasodilatory eicosanoid generated from arachidonic acid by cytochrome P450 epoxygenases. A series of robust, partially saturated analogues containing epoxide bioisosteres were synthesized and evaluated for relaxation of precontracted bovine coronary artery rings and for in vitro inhibition of soluble epoxide hydrolase (sEH). Depending upon the bioisostere and its position along the carbon chain, varying levels of vascular relaxation and/or sEH inhibition were observed. For example, oxamide 16 and N-iPr-amide 20 were comparable (ED50 1.7 μM) to 14,15-EET as vasorelaxants but were approximately 10-35 times less potent as sEH inhibitors (IC50 59 and 19 μM, respectively); unsubstituted urea 12 showed useful activity in both assays (ED50 3.5 μM, IC50 16 nM). These data reveal differential structural parameters for the two pharmacophores that could assist the development of potent and specific in vivo drug candidates.",
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AU - Capdevila, Jorge H.

AU - Yi, Xiu Yu

AU - Goldman, Daniel H.

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AU - Campbell, William B.

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