Structure-Activity Relationship Study and Biological Evaluation of 2-(Disubstituted phenyl)-indole-5-propanoic Acid...

G-protein-coupled receptor 40 (GPR40) is considered as an attractive drug target for treating type 2 diabetes, owing to its role in the free fatty acid-mediated increase in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To identify a new chemotype of GPR40 agonist, a series of 2-aryl-substituted indole-5-propanoic acid derivatives were designed and synthesized. We identified two GPR40 agonist lead compounds-4k (3-[2-(4-fluoro-2-methylphenyl)-1H-indol-5-yl]propanoic acid) and 4o (3-[2-(2,5-dimethylphenyl)-1H-indol-5-yl]propanoic acid), having GSIS and glucagon-like peptide 1 secretory effects. Unlike previously reported GPR40 partial agonists that only activate the G_q pathway, 4k and 4o activated both the G_q and G_s signaling pathways and were characterized as GPR40 full agonists. In in vivo efficacy studies, 4o significantly improved glycemic control in both C57BL/6J and db/db mice and increased plasma-active GLP-1 in C57BL/6J mice. Thus, 4o represents a promising lead for further development as a novel GPR40 full agonist against type 2 diabetes.