口服GLP-1R激动剂的含硒衍生物的发现

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-01-17 DOI:10.1021/acs.jmedchem.4c02616

Xuetao Chen, Shicheng Xu, Shuang Yang, Zezhou Yu, Yali Chen, Huidan Wu, Qichao Bao, Qidong You, Xiaoke Guo, Zhengyu Jiang

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引用次数: 0

摘要

胰高血糖素样肽-1受体（GLP-1R）是治疗2型糖尿病（T2DM）和肥胖的公认靶点。开发具有口服生物利用度和长效的小分子GLP-1R激动剂是学术界和工业界的共同追求。本文采用硒氧生物等异体策略在丹格列酮支架上设计了新的含硒化合物。其中，化合物21具有口服生物利用性，具有促进环磷酸腺苷（cAMP）积累的充分拮抗作用。在hGLP-1R敲入的小鼠中，21有效地降低了血糖水平和食物摄入量，与danuglipron相比，作用时间略有延长。重要的是，在亚急性毒性研究中，未观察到21对小鼠的显著不良反应。本研究描述了含硒化合物作为口服GLP-1R激动剂的潜力，其中化合物21有望成为治疗2型糖尿病和肥胖的候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

查看原文本刊更多论文

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

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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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.