1104443-16-4Relevant articles and documents
Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1 H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119
Wacker, Dean A.,Wang, Ying,Broekema, Matthias,Rossi, Karen,Oconnor, Steven,Hong, Zhenqiu,Wu, Ginger,Malmstrom, Sarah E.,Hung, Chen-Pin,Lamarre, Linda,Chimalakonda, Anjaneya,Zhang, Lisa,Xin, Li,Cai, Hong,Chu, Cuixia,Boehm, Stephanie,Zalaznick, Jacob,Ponticiello, Randolph,Sereda, Larisa,Han, Song-Ping,Zebo, Rachel,Zinker, Bradley,Luk, Chiuwa Emily,Wong, Richard,Everlof, Gerry,Li, Yi-Xin,Wu, Chunyu K.,Lee, Michelle,Griffen, Steven,Miller, Keith J.,Krupinski, John,Robl, Jeffrey A.
, p. 7499 - 7508 (2014/12/11)
G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-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.
