Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

ACS Med Chem Lett. 2015 Nov 20;7(1):51-5. doi: 10.1021/acsmedchemlett.5b00323. eCollection 2016 Jan 14.


TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg.

Keywords: GLP1 secretion; GPBAR1; GPR 131; TGR5; TGR5 agonist; diabetes.