Structure-Activity Relationship Study and Biological Evaluation of 2-(Disubstituted phenyl)-indole-5-propanoic Acid Derivatives as GPR40 Full Agonists

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 Gq pathway, 4k and 4o activated both the Gq and Gs 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.