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.