Design of potent and selective GPR119 agonists for type II diabetes

…, AD Adams, G Chicchi, S Freeman, AD Howard…

Index: Szewczyk, Jason W.; Acton, John; Adams, Alan D.; Chicchi, Gary; Freeman, Stanley; Howard, Andrew D.; Huang, Yong; Li, Cai; Meinke, Peter T.; Mosely, Ralph; Murphy, Elizabeth; Samuel, Rachel; Santini, Conrad; Yang, Meng; Zhang, Yong; Zhao, Kake; Wood, Harold B. Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 9 p. 2665 - 2669

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Citation Number: 22

Abstract

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC50= 3600nM). 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 ...