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.