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-<i>cis</i>-CF₃ to the pyrrolidine improves the human GPR40 binding <i>K</i>_i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers <b>(</b><i><b>R,R</b></i><b>)-68</b> and <b>(</b><i><b>S,S</b></i><b>)-68</b> have differential effects on the radioligand used for the binding assay, with <b>(</b><i><b>R,R</b></i><b>)-68</b> potentiating the radioligand and <b>(</b><i><b>S,S</b></i><b>)-68</b> displacing the radioligand. Compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> activates both G_q-coupled intracellular Ca²⁺ flux and G_s-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b>, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series