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

详细信息    查看全文

• 作者：Hong C. Shen ; Fa-Xiang Ding ; Qiaolin Deng ; Suoyu Xu ; Xinchun Tong ; Xiaoping Zhang ; Yuli Chen ; Gaochao Zhou ; Lee-Yuh Pai ; Magdalena Alonso-Galicia ; Sophie Roy ; Bei Zhang ; James R. Tata ; Joel P. Berger
• 关键词：Amide mimics ; Aminoheterocycles ; Inhibitors ; sEH ; Soluble epoxide hydrolase
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：1 October 2009
• 年：2009
• 卷：19
• 期：19
• 页码：5716-5721
• 全文大小：2542 K

文摘

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.