Discovery of New Difluorocyclobutyl Derivatives as Effective Glucagon-Like Peptide-1 Receptor Agonists with Reduced hERG Inhibitory Activities

Danuglipron (PF-06882961), a small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) developed by Pfizer, has shown significant potential to reduce blood glucose levels and weight in patients with type 2 diabetes mellitus. However, it has moderate hERG inhibitory activities (IC₅₀ = 4.3 μM), potentially conferring a risk for cardiac toxicity. Here, we report a new class of difluorocyclobutyl derivatives that can be used to reduce the potential hERG inhibition caused by the piperidine ring of danuglipron. After in vitro and in vivo screening, compound 73 was found to be the most potent GLP-1R agonist, with an EC₅₀ of 0.048 nM. Furthermore, compound 73 showed preferable absorption and excellent β-arrestin pathway selectivity compared with danuglipron. In the glucose tolerance test, compound 73 effectively inhibited elevated blood glucose levels. These results indicate that compound 73 is a promising GLP-1R agonist.