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 Med Chem 2009 Aug 27;52(16):5069-75
Date
08/06/2009Pubmed ID
19653681Pubmed Central ID
PMC2888647DOI
10.1021/jm900634wScopus ID
2-s2.0-69049118113 (requires institutional sign-in at Scopus site) 80 CitationsAbstract
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 (ED(50) 1.7 microM) to 14,15-EET as vasorelaxants but were approximately 10-35 times less potent as sEH inhibitors (IC(50) 59 and 19 microM, respectively); unsubstituted urea 12 showed useful activity in both assays (ED(50) 3.5 microM, IC(50) 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.
Author List
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 WBAuthor
William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAnimals
Cattle
Coronary Vessels
Epoxide Hydrolases
Epoxy Compounds
Humans
In Vitro Techniques
Isometric Contraction
Recombinant Proteins
Solubility
Stereoisomerism
Structure-Activity Relationship
Vasodilation
Vasodilator Agents
