Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties.
Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties.
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DOI：
10.1021/jm101087u
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发表时间：
2010-12-09
影响因子：
7.3
通讯作者：
Long YQ
中科院分区：
文献类型：
--
作者：
Huang SX;Li HY;Liu JY;Morisseau C;Hammock BD;Long YQ
抑制哺乳动物可溶性环氧化物水解酶（sEH）是治疗高血压、炎症和其他疾病的一种有前景的新疗法。然而，有限的水溶性、高熔点和低代谢稳定性的问题使1,3-二取代脲基sEH抑制剂的发展变得复杂。目前的研究探索了取代哌嗪基作为第三药效团的引入，与先前报道的基于1-金刚烷基尿素的抑制剂相比，在保持高效的同时，其药代动力学参数得到了实质性的改善。SAR研究表明，间取代或对取代苯基间隔剂和n4 -乙酰基或磺酰基取代哌嗪是获得高效能和良好物理性能的最佳结构。1-(4-（4-（4-（4-乙酰哌嗪-1-酰基）丁氧基）苯基）-3-金刚烷-1-酰基尿素（29c）在小鼠体内具有良好的药动学特性：T1/2 =14 h, Cmax = 84 nM, AUC = 40200 nM•min，对人sEH酶的IC50值为7.0 nM。
The inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation and other disorders. However, the problems of limited water solubility, high melting point and low metabolic stability complicated the development of 1,3-disubstituted urea-based sEH inhibitors. The current study explored the introduction of the substituted piperazino group as the tertiary pharmacophore, which resulted in substantial improvements in pharmacokinetic parameters over previously reported 1-adamantyl-urea based inhibitors while retaining high potency. The SAR studies revealed that the meta- or para-substituted phenyl spacer, and N4-acetyl or sulfonyl substituted piperazine were optimal structures for achieving high potency and good physical properties. The 1-(4-(4-(4-acetylpiperazin-1-yl)butoxy)phenyl)-3-adamantan-1-yl urea (29c) demonstrated excellent in vivo pharmacokinetic properties in mice: T1/2 =14 h, Cmax = 84 nM and AUC = 40200 nM • min with an IC50 value of 7.0 nM against human sEH enzyme.
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