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 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 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.