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 <b>73</b> was found to be the most potent GLP-1R agonist, with an EC₅₀ of 0.048 nM. Furthermore, compound <b>73</b> showed preferable absorption and excellent β-arrestin pathway selectivity compared with danuglipron. In the glucose tolerance test, compound <b>73</b> effectively inhibited elevated blood glucose levels. These results indicate that compound <b>73</b> is a promising GLP-1R agonist.