Design of potent and selective GPR119 agonists for type II diabetes

✍ Scribed by Jason W. Szewczyk; John Acton; Alan D. Adams; Gary Chicchi; Stanley Freeman; Andrew D. Howard; Yong Huang; Cai Li; Peter T. Meinke; Ralph Mosely; Elizabeth Murphy; Rachel Samuel; Conrad Santini; Meng Yang; Yong Zhang; Kake Zhao; Harold B. Wood

• Book ID: 104005260
• Publisher: Elsevier Science
• Year: 2011
• Tongue: English
• Weight: 596 KB
• Volume: 21
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.12.086

✦ Synopsis

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).