1 research outputs found
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>-CF<sub>3</sub> to the pyrrolidine improves the human GPR40 binding <i>K</i><sub>i</sub> 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<sub>q</sub>-coupled intracellular Ca<sup>2+</sup> flux and G<sub>s</sub>-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