GPR40 (G protein-coupled receptor 40) has become an attractive target for insulin secretagogue via glucose-dependent mechanism with low risk of hypoglycemia. In order to overcome problems associated with previously developed GPR40 agonists, we recruited the core fragment 2,3-dihydro-1H-indene to GPR40 receptor binding pharmacophore with carboxylic acid moiety, and screened various amine analogs to finally discover several hit compounds displaying GPR40 agonistic activities. Through additional in vitro ADME, pharmacokinetics, and in vivo efficacy evaluations, compound 1e was demonstrated as a potent lead GPR40 agonist.
- Glucose-stimulated insulin secretion
- Insulin secretagogue