A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors

被引:34
作者
Shen, Hong C. [1 ]
Ding, Fa-Xiang [1 ]
Deng, Qiaolin [1 ]
Xu, Suoyu [2 ]
Tong, Xinchun [2 ]
Zhang, Xiaoping [3 ]
Chen, Yuli [3 ]
Zhou, Gaochao [3 ]
Pai, Lee-Yuh [4 ]
Alonso-Galicia, Magdalena [4 ]
Roy, Sophie [4 ]
Zhang, Bei [3 ]
Tata, James R. [1 ]
Berger, Joel P. [3 ]
Colletti, Steven L. [1 ]
机构
[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA
[3] Merck Res Labs, Dept Metab Disorders, Rahway, NJ 07065 USA
[4] Merck Res Labs, Dept Cardiovasc Dis, Rahway, NJ 07065 USA
关键词
Amide mimics; Aminoheterocycles; Inhibitors; sEH; Soluble epoxide hydrolase; EPOXYGENASE-DERIVED EICOSANOIDS; UREA-BASED INHIBITORS; EPOXYEICOSATRIENOIC ACIDS; ARACHIDONIC-ACID; WATER SOLUBILITY; BLOOD-PRESSURE; CYTOCHROME-P450; HYPERTENSION; METABOLISM; PROTECTION;
D O I
10.1016/j.bmcl.2009.08.006
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationship (SAR) study was focused on improving the sEH inhibitory activity. Aminobenzisoxazoles emerged to be the optimal series, of which a potent human sEH inhibitor 7t was identified with a good pharmacokinetics (PK) profile. The strategy of employing aminoheterocycles as amide replacements may represent a general approach to develop mimics of known hydrolase or protease inhibitors containing an amide moiety. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5716 / 5721
页数:6
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