Orally bioavailable potent soluble epoxide hydrolase inhibitors
Orally bioavailable potent soluble epoxide hydrolase inhibitors
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DOI：
10.1021/jm070270t
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发表时间：
2007-08-09
影响因子：
7.3
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
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作者：
Hwang, Sung Hee;Tsai, Hsing-Ju;Hammock, Bruce D.
制备了一系列N,N'-二取代脲，其具有构象限制的顺式-或反式-1,4-环己烷α，并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，这些新的有效抑制剂比之前描述的 sEH 抑制剂表现出更高的体内代谢稳定性。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) 在狗体内具有出色的口服生物利用度 (98%，n = 2) 和血液曲线下面积，并且在体内可有效治疗脂多糖攻击的小鼠模型中的低血压。
A series of N,N'-disubstituted ureas having a conformationally restricted cis- or traiis-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.