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 <b>29</b> (DA-302168S), which exhibits higher potency both <i>in vitro</i>/<i>in</i> <i>vivo</i> 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 IC₅₀ > 30 μM and no significant off-target toxicity. Its favorable pharmacokinetics support once-daily oral dosing, improving patient compliance. These findings suggest that compound <b>29</b> 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.