Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide‑1 Receptor Agonists

Danuglipron is the most representative
small-molecule agonist of
the glucagon-like peptide-1 receptor (GLP-1R) and has received considerable
attention due to positive results in the treatment of type 2 diabetes
mellitus (T2DM) and obesity in clinical trials. However, hERG inhibition,
lower activity than endogenous GLP-1, and a short action time represent
limitations in terms of feasible application. In this study, we report
a new class of 5,6-dihydro-1,2,4-triazine derivatives that serve to
eliminate potential hERG inhibition caused by the piperidine ring
of danuglipron. Applying systematic in vitro to in vivo screening,
we have identified compound 42 as a highly potent and
selective GLP-1R agonist, which delivers improved (7-fold) efficacy
in stimulating cAMP accumulation compared with danuglipron and which
exhibits acceptable drug-like properties. Furthermore, 42 significantly reduces glucose excursion and inhibits food intake
of hGLP-1R Knock-In mice. These effects are longer-lasting than that
shown by danuglipron, demonstrating feasibility in the treatment of
T2DM and obesity.