Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes

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• 作者：Ping Liu ; Zhiyong Hu ; Byron G. DuBois ; Christopher R. Moyes ; David N. Hunter ; Cheng Zhu ; Nam Fung Kar ; Yuping Zhu ; Joie Garfunkle ; Ling Kang ; Gary Chicchi ; Anka Ehrhardt ; Andrea Woods ; Toru Seo ; Morgan Woods ; Margaret van Heek ; Karen H. Dingley ; Jianmei Pang ; Gino M. Salituro ; Joyce Powell ; Jenna L. Terebetski ; Viktor Hornak ; Louis-Charles Campeau ; Joe Lamberson ; Fez Ujjainwalla ; Michael Miller ; Andrew Stamford ; Harold B. Wood ; Timothy Kowalski ; Ravi P. Nargund ; Scott D. Edmondson
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：936-941
• 全文大小：389K
• ISSN：1948-5875

文摘

We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT.