Hwang Sung Hee, Tsai Hsing-Ju, Liu Jun-Yan, Morisseau Christophe, Hammock Bruce D
Department of Entomology and UCD Cancer Center, University of California-Davis, One Shields Avenue, Davis, CA 95616-8584, USA.
J Med Chem. 2007 Aug 9;50(16):3825-40. doi: 10.1021/jm070270t. Epub 2007 Jul 6.
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.
制备了一系列在脲的α位具有构象受限的顺式或反式-1,4-环己烷的N,N'-二取代脲，并将其作为可溶性环氧化物水解酶（sEH）抑制剂进行测试。该系列化合物对重组人sEH表现出低纳摩尔至皮摩尔的活性。两种异构体显示出相似的效力，但反式异构体在人肝微粒体中代谢更稳定。此外，这些新型强效抑制剂在体内比先前描述的sEH抑制剂具有更高的代谢稳定性。我们证明反式-4-[4-(3-金刚烷-1-基脲基)环己氧基]苯甲酸13g（t-AUCB，IC50 = 1.3 +/- 0.05 nM）在犬类中具有优异的口服生物利用度（98%，n = 2）和血药浓度-时间曲线下面积，并且在体内对脂多糖攻击的小鼠模型中的低血压治疗有效。
