Structural refinement of inhibitors of urea-based soluble epoxide hydrolases
Structural refinement of inhibitors of urea-based soluble epoxide hydrolases
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DOI：
10.1016/s0006-2952(02)00952-8
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发表时间：
2002-05-01
影响因子：
5.8
通讯作者：
Hammock, BD
中科院分区：
文献类型：
--
作者：
Morisseau, C;Goodrow, MH;Hammock, BD
可溶性环氧化物水解酶（sEH）参与花生四烯酸、亚油酸和其他脂肪酸环氧化物的代谢，这些脂肪酸环氧化物是在血压调节和炎症中起重要作用的内源性化学介质。1，3-二取代脲、氨基甲酸酯和酰胺是新的有效且稳定的sEH抑制剂。然而，先导化合物的溶解性差限制了它们的应用。研究了抑制剂结构-活性关系，以更好地定义抑制的结构要求，并确定分子拓扑中可以接受极性基团而不降低抑制效力的点。结果表明，亲脂性是控制抑制剂效力的重要因素。如果极性基团被放置在离脲官能团足够远的距离处，则它们可以被引入到烷基基团之一中而不损失活性。所得化合物具有2倍更高的水溶性。这些发现将有助于合理设计和优化具有更好物理性质的sEH抑制剂。(C)2002年由Elsevier Science Inc.出版
The soluble epoxide hydrolase (sEH) is involved in the metabolism of arachidonic, linoleic, and other fatty acid epoxides, endogenous chemical mediators that play an important role in blood pressure regulation and inflammation. 1,3-Disubstituted ureas, carbamates, and amides are new potent and stable inhibitors of sEH. However, the poor solubility of the lead compounds limits their use. Inhibitor structure-activity relationships were investigated to better define the structural requirements for inhibition and to identify points in the molecular topography that could accept polar groups without diminishing inhibition potency. Results indicate that lipophilicity is an important factor controlling inhibitor potency. Polar groups could be incorporated into one of the alkyl groups without loss of activity if they were placed at a sufficient distance from the urea function. The resulting compounds had a 2-fold higher water solubility. These findings will facilitate the rational design and optimization of sEH inhibitors with better physical properties. (C) 2002 Published by Elsevier Science Inc.