Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold

The
free fatty acid receptor GPR40 is predominantly expressed in
pancreatic β-cells and enhances insulin secretion in a glucose
dependent manner. Therefore, GPR40 agonists are possible novel insulin
secretagogues with reduced or no risk of hypoglycemia for the treatment
of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse
GPR40 agonists with high safety are pursued for the clinical development
of GPR40-based pharmacotherapeutics. Herein we report our design and
discovery of a new chemotype of GPR40 agonists free of the typical
phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing
GPR40 modulators functioned as full agonists with high-efficacy response
(Emax) and reduced lipophilicity. Significantly,
the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion
and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40
partial agonist TAK-875, which was once in phase III
clinical trials, and high selectivity over the relevant receptors
GPR120 and PPARγ.