GPR40 is a G-protein coupled receptor for long-chain fatty acids which is expressed in pancreatic beta cells and enteroendocrine cells in the gastrointestinal tract. The receptor can contribute considerably to overall glycemic control by acting directly on pancreatic �-cells to enhance glucose-stimulated insulin secretion and by stimulating the release of incretins (GLP-1, GIP) from enteroendocrine cells. Throughout the discovery program, efforts were made to advance the chemotype via increases in polarity (log P), SP3 character, and chirality with the goal of reduced off-target activity. These efforts led to the optimization of a dihydropyrazole series of GPR40 agonists culminating in the discovery of BMS-986118, which has been extensively characterized in vitro and in preclinical in vivo models of diabetes.

Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion

248th National Meeting (2014)

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