Discovery of 5-Chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an Antidiabetic Clinical Candidate Targeting GPR119

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• 作者：Dean A. Wacker ; Ying Wang ; Matthias Broekema ; Karen Rossi ; Steven O鈥機onnor ; Zhenqiu Hong ; Ginger Wu ; Sarah E. Malmstrom ; Chen-Pin Hung ; Linda LaMarre ; Anjaneya Chimalakonda ; Lisa Zhang ; Li Xin ; Hong Cai ; Cuixia Chu ; Stephanie Boehm ; Jacob Zalaznick ; Randolph Ponticiello ; Larisa Sereda ; Song-Ping Han ; Rachel Zebo ; Bradley Zinker ; Chiuwa Emily Luk ; Richard Wong ; Gerry Everlof ; Yi-Xin Li ; Chunyu K. Wu ; Michelle Lee ; Steven Griffen ; Keith J. Miller ; John Krupinski ; Jeffrey A. Robl
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 25, 2014
• 年：2014
• 卷：57
• 期：18
• 页码：7499-7508
• 全文大小：470K
• ISSN：1520-4804

文摘

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic 尾-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.