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

  • J Med Chem. 2014 Sep 25;57(18):7499-508. doi: 10.1021/jm501175v.
Dean A Wacker  1 ,  Ying Wang ,  Matthias Broekema ,  Karen Rossi ,  Steven O'Connor ,  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
Affiliations
  • 1. Departments of Discovery Chemistry, Metabolic Diseases, Lead Evaluation, Computer-Assisted Drug Design, Discovery Toxicology, Exploratory Clinical and Translational Research, and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
PMID: 25208139 DOI: 10.1021/jm501175v
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.

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