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

  • J Med Chem. 2025 May 8;68(9):9555-9583. doi: 10.1021/acs.jmedchem.5c00242.
Guangxin Dong  1 ,  Qijun Ye  1 ,  Wenwen Li  1 ,  Shaofeng Zhang  1 ,  Zhenyu Yang  2 ,  Rui Zhang  1 ,  Ta Deng  1 ,  Haiyan Li  1 ,  Yong Zhang  1 ,  Xiaojie Zhang  1 ,  Shucheng He  1 ,  Daoheng Zhou  1 ,  Juan Zhang  1 ,  Peng He  1 ,  Zhou Yu  1 ,  Yi Li  1
Affiliations
  • 1. Chengdu DIAO Pharmaceutical Group Co., Ltd., Chengdu 610041, China.
  • 2. West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 40257122 DOI: 10.1021/acs.jmedchem.5c00242
Abstract

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.

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