Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist

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• 作者：Sean P. Brown ; Paul J. Dransfield ; Marc Vimolratana ; XianYun Jiao ; Liusheng Zhu ; Vatee Pattaropong ; Ying Sun ; Jinqian Liu ; Jian Luo ; Jane Zhang ; Simon Wong ; Run Zhuang ; Qi Guo ; Frank Li ; Julio C. Medina ; Gayathri Swaminath ; Daniel C.-H. Lin ; Jonathan B. Houze
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：3
• 期：9
• 页码：726-730
• 全文大小：351K
• 年卷期：v.3,no.9(September 13, 2012)
• ISSN：1948-5875

文摘

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.

Keywords:

GPR40; full agonist; AM-1638; AMG 837; insulin secretagogue; FFA1