Activation of Glucagon-like peptide-1 receptor (GLP-1R) by peptides has been proven clinically to be a very effective treatment approach for type 2 diabetes (T2D) and obesity. Here we describe a small molecule GLP-1R full agonist RGT-075 identified through Computer Accelerated Rational Design (CARD) (Ma et al., Cell Research 2020) with nM potency in G-protein coupled cAMP signaling. RGT-075 displayed much reduced activity in receptor-mediated β-arrestin recruitment and subsequent internalization. It was shown to be selective against other class B G protein-coupled receptors (GPCRs) and was only active for human and monkey GLP-1R. It demonstrated favorable oral bioavailability and pharmacodynamic profile for once-daily oral dosing in monkeys. In food-induced glucose intolerant and prediabetic cynomolgus monkeys, oral administration of RGT-075 improved glucose tolerance to a level comparable to injectable liraglutide. In food-induced type 2 diabetic monkeys, once-daily oral administration of RGT-075 reduced food intake and fasting plasma glucose levels. Together, these data support the development and advancement of RGT-075 into the clinic as a potential therapeutic for T2D and obesity.
F.Liu: Employee; Regor Pharmaceuticals Inc. X.Sun: Employee; AutoDrug Biotech Co. Ltd., Qilu Regor Therapeutics Inc. W.Huang: None. W.Guo: None. J.Lin: None. W.Zhong: None.