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.
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.
authors.affiliation: 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.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Wacker
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Matthias
authors.initials: M
authors.lastname: Broekema
authors.forename: Karen
authors.initials: K
authors.lastname: Rossi
authors.forename: Steven
authors.initials: S
authors.lastname: O'Connor
authors.forename: Zhenqiu
authors.initials: Z
authors.lastname: Hong
authors.forename: Ginger
authors.initials: G
authors.lastname: Wu
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Malmstrom
authors.forename: Chen-Pin
authors.initials: CP
authors.lastname: Hung
authors.forename: Linda
authors.initials: L
authors.lastname: LaMarre
authors.forename: Anjaneya
authors.initials: A
authors.lastname: Chimalakonda
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Xin
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.forename: Cuixia
authors.initials: C
authors.lastname: Chu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boehm
authors.forename: Jacob
authors.initials: J
authors.lastname: Zalaznick
authors.forename: Randolph
authors.initials: R
authors.lastname: Ponticiello
authors.forename: Larisa
authors.initials: L
authors.lastname: Sereda
authors.forename: Song-Ping
authors.initials: SP
authors.lastname: Han
authors.forename: Rachel
authors.initials: R
authors.lastname: Zebo
authors.forename: Bradley
authors.initials: B
authors.lastname: Zinker
authors.forename: Chiuwa Emily
authors.initials: CE
authors.lastname: Luk
authors.forename: Richard
authors.initials: R
authors.lastname: Wong
authors.forename: Gerry
authors.initials: G
authors.lastname: Everlof
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Li
authors.forename: Chunyu K
authors.initials: CK
authors.lastname: Wu
authors.forename: Michelle
authors.initials: M
authors.lastname: Lee
authors.forename: Steven
authors.initials: S
authors.lastname: Griffen
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Miller
authors.forename: John
authors.initials: J
authors.lastname: Krupinski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D011728:Pyridones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D013450:Sulfones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C000593257:5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D011728:Pyridones; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones