GPR119 is a G protein-coupled receptor expressed predominantly in pancreatic b-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 GI tract. GLP-1 has well-established anti-diabetic effects. 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. We have identified a novel class of GPR119 agonists based on a bicyclic pyrimidine core, exemplified by isopropyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenyl)amino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate (1  ). Herein, we describe the discovery, structure-activity relationships (SAR) and in vivo studies of this and related chemotypes.

Synthesis and SAR of bicyclic pyrimidines as GPR119 receptor agonists

244th National Meeting (2012)

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