2. Academic Validation
  3. Discovery of Selenium-Containing Derivatives as Potent and Orally Bioavailable GLP-1R Agonists

Discovery of Selenium-Containing Derivatives as Potent and Orally Bioavailable GLP-1R Agonists

  • J Med Chem. 2025 Feb 13;68(3):3386-3408. doi: 10.1021/acs.jmedchem.4c02616.
Xuetao Chen 1 2,  Shicheng Xu 1 2,  Shuang Yang 1 2,  Zezhou Yu 1 2,  Yali Chen 1 2,  Huidan Wu 1 2,  Qichao Bao 1 2,  Qidong You 1 2,  Xiaoke Guo 1 2,  Zhengyu Jiang 1 2
Affiliations

Affiliations

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 39824521 DOI: 10.1021/acs.jmedchem.4c02616
Abstract

Glucagon-like peptide-1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. The development of orally bioavailable and long-acting small-molecule GLP-1R agonists is a pursuit in both academia and industry. Herein, new selenium (Se)-containing compounds were designed using a Se-oxygen bioisostere strategy on the danuglipron scaffold. Among these, compound 21 was orally bioavailable and exhibited full agonistic efficacy in promoting cyclic adenosine monophosphate (cAMP) accumulation. In hGLP-1R knock-in mice, 21 effectively reduced blood glucose levels and food intake, with the duration of action slightly extended compared to that of danuglipron. Importantly, no significant adverse effects were observed in mice treated with 21 during the subacute toxicity studies. This study delineates the potential of Se-containing compounds as orally bioavailable GLP-1R agonists, with compound 21 emerging as a promising candidate for T2DM and obesity treatment.

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