SAR Studies of Indole-5-propanoic Acid Derivatives To Develop Novel GPR40 Agonists

G-protein coupled receptor 40 (GPR40) has been considered to be an attractive drug target for the treatment of type 2 diabetes because of its role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. A series of indole-5-propanoic acid compounds were synthesized, and their GPR40 agonistic activities were evaluated by nuclear factor of activated T-cells reporter assay and GSIS assay in the MIN-6 insulinoma cells. Three compounds, 8h (EC₅₀ = 58.6 nM), 8i (EC₅₀ = 37.8 nM), and 8o (EC₅₀ = 9.4 nM), were identified as potent GPR40 agonists with good GSIS effects.