Chapter Six - Small-Molecule Modulators of GPR40 (FFA1)

Abstract GPR40 (also known as FFA1) is a G-protein-coupled receptor primarily expressed in pancreatic islets and enteroendocrine cells, and activation of GPR40 has been shown to stimulate insulin secretion through a glucose-dependent mechanism. For this reason, the pharmaceutical industry has focused considerable resources on small-molecule GPR40 activators as a potential treatment for type II diabetes. This chapter details the important GPR40 activators disclosed to date, particularly focusing on clinical candidates. Additionally, two distinct classes of GPR40 activators have been discovered that bind in discreet allosteric binding pockets: partial agonists and full agonists. The differences in both chemical structure and biological efficacy between these two classes of GPR40 ligands are discussed in detail.