2. Academic Validation
  3. 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

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

Affiliation

  • 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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