The G-protein-coupled receptor 40 (GPR40) mediates fatty acid-induced insulin secretion from pancreatic β-cells. The crystal structures of GPR40 bound to several different synthetic agonists have revealed the existence of multiple allosteric ligand-binding pockets. The GPR40 partial agonists bind to a site within the outer cell membrane (PDB ID: 4PHU) while the full agonists bind in a lipid-facing binding pocket outside the transmembrane helical bundle on the GPR40 receptor (PDB ID: 5TZY). Among the many GPR40 agonists that have been reported, the most advanced, fasiglifam, is a GPR40 partial agonist that stimulates IP1 and improves glycemic control in diabetic patients via glucose-dependent insulin secretion (ca. 1% decrease in HbA1c). Recently, a novel GPR40 full agonist (Compound A) was discovered that stimulates IP1 and cAMP and results in both insulin and glucagon-like peptide-1 (GLP-1) secretion. Chronic treatment with Compound A dose-dependently reduced body weight (-7% and -15% at 10 and 30 mg/kg) and improved glucose metabolism in diet-induced obese (DIO) mice. Notably, Compound A also dose-dependently increases insulin secretion in ex vivo Type 2 diabetic human islets. The chemical synthesis, SAR, binding, signaling and relevant biological data will be presented.

Cyclohexyl GPR40 full agonists for the treatment of type 2 diabetes

255th National Meeting (2018)

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