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

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-CF3 to the pyrrolidine improves the human GPR40 binding Ki 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
Gq-coupled intracellular Ca2+ flux and Gs-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.