TY - JOUR
T1 - 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates
T2 - Carboxylate modifications
AU - Falck, J R
AU - Koduru, Sreenivasulu Reddy
AU - Mohapatra, Seetaram
AU - Manne, Rajkumar
AU - Atcha, Raju
AU - Manthati, Vijaya L.
AU - Capdevila, Jorge H.
AU - Christian, Sarah
AU - Imig, John D.
AU - Campbell, William B.
PY - 2014/8/28
Y1 - 2014/8/28
N2 - 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.
AB - 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.
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U2 - 10.1021/jm500262m
DO - 10.1021/jm500262m
M3 - Article
C2 - 25119815
AN - SCOPUS:84906871712
SN - 0022-2623
VL - 57
SP - 6965
EP - 6972
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -