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
| Autor: | Gerry Everlof, Chen-Pin Hung, Bradley A. Zinker, Ginger Wu, Steven C. Griffen, Stephanie Boehm, Hong Cai, Larisa Sereda, Li Xin, Matthias Broekema, Linda LaMarre, Sarah E. Malmstrom, Randolph P. Ponticiello, Cuixia Chu, Anjaneya Chimalakonda, Jeffrey A. Robl, Chiuwa Emily Luk, Michelle Lee, Steven O’Connor, Rachel Zebo, Keith J. Miller, Ying Wang, Richard L. Wong, John Krupinski, Zhenqiu Hong, Lisa Zhang, Jacob Zalaznick, Songping Han, Chunyu K. Wu, Yi-Xin Li, Karen A. Rossi, Dean A. Wacker |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Models Molecular Protein Conformation Pyridones medicine.medical_treatment Incretin Enteroendocrine cell Pharmacology Receptors G-Protein-Coupled Rats Sprague-Dawley Mice In vivo Drug Discovery medicine Animals Hypoglycemic Agents Molecular Targeted Therapy Sulfones Receptor Clinical Trials as Topic Gastrointestinal tract Chemistry Insulin Rats medicine.anatomical_structure GPR119 Diabetes Mellitus Type 2 Drug Design Molecular Medicine Pancreas |
| Zdroj: | Journal of Medicinal Chemistry. 57:7499-7508 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm501175v |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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