Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase.
Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase.
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DOI：
10.1039/c2md00288d
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发表时间：
2012-03-01
期刊：
影响因子：
--
通讯作者：
Long YQ
中科院分区：
文献类型：
--
作者：
Huang SX;Cao B;Morisseau C;Jin Y;Hammock BD;Long YQ
可溶性环氧化物水解酶（sEH）的抑制是治疗高血压、炎症和其他心血管疾病的一种有前途的新疗法。哌嗪基功能作为三级药效基团显着改善了 1,3-二取代脲 sEH 抑制剂的药物特性。然而，效力更多地取决于亲水性和亲脂性的总体最佳平衡。基于sEH抑制剂复合物结构，对含哌嗪基的1,3-二取代尿素支架进行了进一步的结构优化，以提高其效力。 1-金刚烷基乙酰胺和对苯基羰基分别被确定为最佳的主要药效团和次要药效团基序，产生具有良好水溶性的亚纳摩尔 sEH 抑制剂。
The inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation and other cardiovascular disorders. Piperazino functionality as the tertiary pharmacophore remarkably improved the drug-like profile of the 1,3-disubstituted urea sEH inhibitors. However, the potency was more dependent on the overall best balance of the hydrophilicity and lipophilicity. Based on the sEH-inhibitor complex structure, further structural optimization on the piperazino-containing 1,3-disubstituted urea scaffold was conducted for an improved potency. The 1-adamantylacetamide and para-phenylcarbonyl group were identified to be an optimal primary pharmacophore and secondary pharmacophore motif, respectively, generating sub-nanomolar sEH inhibitors with favorable water solubility.