Ravinder Kodela - 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres: influence upon vascular relaxation and soluble epoxide hydrolase inhibition.

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      Publication Details (including relevant citation   information):

      J. Med. Chem., 2009, 52 (16), pp 5069–5075


      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.

      Address (URL): http://pubs.acs.org/doi/abs/10.1021/jm900634w