GPR40 is a G-protein-coupled receptor (GPCR) activated by endogenous ligands of medium-to-long chain fatty acids. GPR40 is expressed in pancreatic beta-cells and enteroendocrine cells, and it physiologically regulates the secretion of insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP). The strategy to increase insulin secretion, and the activities of GLP-1 and GIP agonism, would be effective in improving diabetes and obesity in humans; hence, GPR40 seems to be highly attractive as a new class of drug for these patients.
GPR40 has three independent small-molecule binding sites. Fasiglifam, a GPR40 partial agonist, binds to one site of these pockets and markedly improves glycemic control by increasing insulin secretion in patients with type 2 diabetes.
SCO-267, identified by SCOHIA researchers and collaborators, is a GPR40 full agonist, which has a new chemical structure and binds to a site independent of the fasiglifam binding site. Contrary to GPR40 partial agonists, which increase insulin secretion only, a GPR40 full agonist such as SCO-267 is unique in that it increases the production of islet hormones and gut hormones. SCO-267 increases the levels of GLP-1, GIP, and peptide YY, and thus, decreases body weight in obesity models. In addition to these hormones, SCO-267 increases insulin secretion and improves glucose control more effectively than GPR40 partial agonists and dipeptidyl peptidase-4 inhibitors. Furthermore, SCO-267 increases the secretion of glucagon, which has a major role in liver metabolism and function, and improves liver parameters in preclinical models with liver-dysfunctions.
Based on these observations, SCO-267 may be a new drug option for the treatment of diabetes, obesity, and non-alcoholic steatohepatitis. A Phase 1 study is ongoing.
Blood glucose level
GLP-1 : Glucagon-like peptide 1
PYY : Peptide YY
GIP : Glucose-dependent insulinotropic peptide