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.

 

Comments:

The study you mentioned focuses on the development of a new class of 5,6-dihydro-1,2,4-triazine derivatives as potential agonists for the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists have shown promise in the treatment of type 2 diabetes mellitus (T2DM) and obesity. However, the previously studied GLP-1R agonist, danuglipron, has certain limitations such as hERG inhibition, lower activity compared to endogenous GLP-1, and a short duration of action.

The researchers aimed to overcome these limitations by synthesizing and testing a new series of compounds. Through systematic in vitro and in vivo screening, they identified compound 42 as a highly potent and selective GLP-1R agonist. Compound 42 exhibited a 7-fold improvement in efficacy in stimulating cAMP accumulation compared to danuglipron. Importantly, it demonstrated acceptable drug-like properties.

Furthermore, in experiments with hGLP-1R Knock-In mice, compound 42 was found to significantly reduce glucose excursion (the increase in blood glucose levels after a meal) and inhibit food intake. These effects were longer-lasting than those observed with danuglipron, indicating the potential of compound 42 for the treatment of T2DM and obesity.

Overall, the study presents a new 5,6-dihydro-1,2,4-triazine derivative, compound 42, as a promising GLP-1R agonist with improved efficacy, selectivity, and duration of action compared to danuglipron. Further research and clinical trials may be needed to explore its potential as a therapeutic option for T2DM and obesity.

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Related Targets

Glucagon Receptor