Discovery and Evaluation of DA-302168S as an Efficacious Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist

Glucagon-like peptide-1 receptor (GLP-1R) holds pivotal importance as a therapeutic target for type 2 diabetes (T2D) and obesity. Several oral small-molecule agonists targeting GLP-1R have been developed to date. Nevertheless, these agonists suffer from several limitations, including low potency, poor pharmacokinetics, and unfavorable safety profiles. Here, we report the discovery of compound 29 (DA-302168S), which exhibits higher potency both in vitro / in vivo while mitigating the risk of drug–drug interaction compared to other reported candidate compounds. Preclinical studies show full efficacy in cAMP activation, glucose reduction, and appetite suppression. Safety assessments reveal minimal risks with hERG IC 50 > 30 μM and no significant off-target toxicity. Its favorable pharmacokinetics support once-daily oral dosing, improving patient compliance. These findings suggest that compound 29 offers a promising therapeutic option for the management of T2D and obesity. Notably, it has successfully completed phase I clinical trials and is currently undergoing phase II clinical trials.