TY - JOUR
T1 - 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres
T2 - Influence upon vascular relaxation and soluble epoxide hydrolase inhibition
AU - Falck, J R
AU - Kodela, Ravinder
AU - Manne, Rajkumar
AU - Atcha, Krishnam Raju
AU - Puli, Narender
AU - Dubasi, Narsimhaswamy
AU - Manthati, Vijay L.
AU - Capdevila, Jorge H.
AU - Yi, Xiu Yu
AU - Goldman, Daniel H.
AU - Morisseau, Christophe
AU - Hammock, Bruce D.
AU - Campbell, William B.
PY - 2009/8/27
Y1 - 2009/8/27
N2 - 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.
AB - 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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U2 - 10.1021/jm900634w
DO - 10.1021/jm900634w
M3 - Article
C2 - 19653681
AN - SCOPUS:69049118113
SN - 0022-2623
VL - 52
SP - 5069
EP - 5075
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -