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.

胰高血糖素样肽-1受体（Glucagon-like peptide-1 receptor, GLP-1R）作为2型糖尿病（type 2 diabetes, T2D）与肥胖的治疗靶点，具有至关重要的临床意义。迄今为止，已有多款靶向GLP-1R的口服小分子激动剂被研发出来，但此类激动剂仍存在诸多局限，包括效力不足、药代动力学特性欠佳以及安全性表现不佳等问题。本研究报道了化合物29（DA-302168S）的发现：相较于已报道的其他候选化合物，该化合物在体外与体内均展现出更高的活性效力，同时可降低药物相互作用风险。临床前研究结果显示，其在环磷酸腺苷（cAMP）激活、血糖降低与食欲抑制方面均可实现完全疗效；安全性评估表明，该化合物的人类钾离子通道hERG半数抑制浓度（IC50）大于30 μM，且未观察到显著脱靶毒性，安全性风险极低。其优良的药代动力学特性支持每日一次口服给药方案，可有效提升患者依从性。上述研究结果表明，化合物29有望成为2型糖尿病与肥胖管理领域极具潜力的治疗选择。值得注意的是，该化合物已顺利完成I期临床试验，目前正处于II期临床试验阶段。