The G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic beta-cells On activation, this receptor enhances the effect of glucose-stimulated insulin secretion (GSIS) via the elevation of intracellular cAMP concentrations Although GPR119 agonists represent promising oral antidiabetic agents for the treatment of type 2 diabetes therapy, they suffer from the inability to adequately directly preserve [beta-cell function To identify a new structural class of small-molecule GPR119 agonists with both GSIS and the potential to preserve function, we screened a library of synthetic compounds and identified a candidate molecule. AS1269574. with a 2,4,6-tri-substituted pyrimidine core Here, we examined the preliminary in vitro and in vivo effects of AS1269574 on insulin secretion and glucose tolerance AS1269574 had an EC50 value of 25 mu M in HEK293 cells transiently expressing human GPRI19 and enhanced insulin secretion in the mouse pancreatic beta-cell line MIN-6 only under high-glucose (16.8 mM) conditions. This contrasted with the action of the sulfonylurea glibenclamicle, which also induced insulin secretion under low-glucose conditions (2 8 mM) In in vivo studies, a single administration of AS1269574 to normal mice reduced blood glucose levels after oral glucose loading based on the observed insulin secretion profiles Significantly. AS1269574 did not affect fed and fasting plasma glucose levels in normal mice Taken together, these results suggest that AS1269574 represents a novel structural class of small molecule, orally administrable G P R I 19 agonists with GSIS and promising potential for the treatment of type 2 diabetes (C) 2010 Elsevier Inc. All rights reserved.