Design and Evaluation of 3‑Phenyloxetane Derivative Agonists of the Glucagon-Like Peptide‑1 Receptor

Various
small molecule GLP1R agonists have been developed
and tested
for treating type 2 diabetes (T2DM) and obesity. However, many of
these new compounds have drawbacks, such as potential hERG inhibition,
lower activity compared to natural GLP-1, limited oral bioavailability
in cynomolgus monkeys, and short duration of action. Recently, a new
category of 3-phenyloxetane derivative GLP1R agonists with enhanced
hERG inhibition has been discovered. Using an AIDD/CADD method, compound 14 (DD202-114) was identified as a potent and
selective GLP1R agonist, which was chosen as a preclinical candidate
(PCC). Compound 14 demonstrates full agonistic efficacy
in promoting cAMP accumulation and possesses favorable drug-like characteristics
compared to the clinical drug candidate Danuglipron. Additionally,
in hGLP-1R knock-in mice, compound 14 displayed a sustained
pharmacological effect, effectively reducing blood glucose levels
and food intake. These findings suggest that compound 14 holds promise as a future treatment option for T2DM and obesity,
offering improved properties.