环氧化物水解酶2
化学
生物利用度
体内
立体化学
环氧化物水解酶
环己烷
酶
微粒体
药理学
异羟肟酸
尿素
苯甲酸
生物化学
有机化学
生物技术
生物
医学
作者
Sung Hee Hwang,Hsing‐Ju Tsai,Jun-Yan Liu,Christophe Morisseau,Bruce D. Hammock
摘要
A series of N,N'-disubstituted ureas having a conformationally restricted cis- or trans-1,4-cyclohexane alpha to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 13g (t-AUCB, IC50 = 1.3 +/- 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models.
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