Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

Abstract

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4- cis -CF 3 to the pyrrolidine improves the human GPR40 binding K i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers ( R,R )-68 and ( S,S )-68 have differential effects on the radioligand used for the binding assay, with ( R,R )-68 potentiating the radioligand and ( S,S )-68 displacing the radioligand. Compound ( R, R )-68 activates both G q -coupled intracellular Ca 2+ flux and G s -coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound ( R, R )-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound ( R, R )-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.