Journal : J. Med. Chem.
Title : 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.
Year : 2014
Volume : 57
Issue : 18
First Page : 7499
Last Page : 7508
Authors : Wacker DA, Wang Y, Broekema M, Rossi K, O'Connor S, Hong Z, Wu G, Malmstrom SE, Hung CP, LaMarre L, Chimalakonda A, Zhang L, Xin L, Cai H, Chu C, Boehm S, Zalaznick J, Ponticiello R, Sereda L, Han SP, Zebo R, Zinker B, Luk CE, Wong R, Everlof G, Li YX, Wu CK, Lee M, Griffen S, Miller KJ, Krupinski J, Robl JA.
Abstract : 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.
