Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

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• 作者：Yingcai Wang ; Jiwen (Jim) Liu ; Paul J. Dransfield ; Liusheng Zhu ; Zhongyu Wang ; Xiaohui Du ; Xianyun Jiao ; Yongli Su ; An-rong Li ; Sean P. Brown ; Annie Kasparian ; Marc Vimolratana ; Ming Yu ; Vatee Pattaropong ; Jonathan B. Houze ; Gayathri Swaminath ; Thanhvien Tran ; Khanh Nguyen ; Qi Guo ; Jane Zhang ; Run Zhuang ; Frank Li ; Lynn Miao ; Michael D. Bartberger ; Tiffany L. Correll ; David Chow ; Simon Wong ; Jian Luo ; Daniel C.-H. Lin ; Julio C. Medina
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：4
• 期：6
• 页码：551-555
• 全文大小：427K
• 年卷期：v.4,no.6(June 13, 2013)
• ISSN：1948-5875

文摘

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure鈥揳ctivity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.

Keywords:

GPR40; full agonist; spirocycles; tricyclic; AM-5262; AM-1638; AMG 837; FFAR1; FFA1