Discovery of GSBR-1290, a Highly Potent, Orally Available, Novel Small Molecule GLP-1 Receptor Agonist

Peptidic glucagon-like peptide 1 receptor agonists (GLP-1RAs) are established treatments for patients with Type 2 Diabetes Mellitus (T2DM) and obesity. However, the need for injection and cold chain storage may limit the utility of most peptidic GLP-1RAs. An oral small molecule GLP-1RA that offers enhanced bioavailability and stability could be more convenient and accessible to patients. Here we report the discovery of GSBR-1290, a highly potent, orally available, novel small molecule GLP-1RA and the characterization of its in vitro and in vivo pharmacology profiles. GSBR-1290 is a small molecule GLP-1RA with high binding affinity to human GLP-1R. GSBR-1290 strongly activated GLP-1R Gαs cAMP pathway without inducing measurable β-arrestin recruitment signaling, which indicates it is a fully biased agonist. The insulin secretion stimulation effect of GSBR-1290 was evaluated in a functional human pancreatic beta cell line, in which GSBR-1290 showed dose dependent induction of insulin secretion. The in vivo efficacy of GSBR-1290 on insulin secretion, glucose control and food intake were evaluated in nonhuman primates (NHPs). In an acute intravenous glucose tolerance test (ivGTT), a single dose of GSBR-1290 strongly induced insulin secretion and glucose clearance. In a repeated dosing study, GSBR-1290 administered orally once daily for 7-day demonstrated robust increase in insulin secretion and glucose clearance in ivGTT and a dose dependent reduction of food intake and body weight. Overall, GSBR-1290 demonstrated potent in vivo efficacy in stimulating insulin secretion, improving glucose tolerance, and reducing food intake and body weight. In conclusion, GSBR-1290 is a highly potent, orally available, fully biased GLP-1RA. Human clinical trials are underway to further evaluate GSBR-1290 as a potential therapy for T2DM and obesity. Disclosure T.Mao: Employee; Structuretx. X.Lin: Employee; Structure Therapeutics. Q.Meng: Employee; Beijing Stonewise Technology, Structure Therapeutics Inc. H.Zhang: Employee; Structuretx. J.J.Zhang: Employee; Structure Therapeutics Inc. S.Shi: Employee; Structure Therapeutics Inc. Z.Guan: Employee; Structure Therapeutics. X.Jiang: Employee; Structure Therapeutics. F.Zhang: Employee; Structure Therapeutics, Eternity BioSciences, Stock/Shareholder; Novo Nordisk. H.Lei: Employee; Structure Therapeutics.