Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor

The discovery, synthesis and structure–activity relationship (SAR) of novel carboxylic acid agonists for GPR40 are described. Aryl propionic acid 1, identified from a high throughput screen, was selected for chemical exploration. Compound 2 was identified as our lead molecule through efficient solid phase combinatorial array chemistry and had an attractive in vitro and in vivo pharmacokinetic profile in rat. These ligands may prove useful in establishing a role for GPR40 in insulin regulation.

Graphical abstractThe discovery, solid phase synthesis and structure–activity relationships of novel carboxylic acid agonists for the GPR40 receptor are described.Figure optionsDownload full-size imageDownload as PowerPoint slide