Synthesis and Activity Evaluation of Novel Benzoxazepinone Derivatives as Potential Inhibitors of Glycogen Phosphorylase

Glycogen phosphorylase (GP) is a key enzyme of glycogen catabolism, so it is significant to discover a new GP inhibitor. A series of benzoxazepinone derivatives were identified as glycogen phosphorylase (GP) inhibitors with potent activity. These compounds exhibited strong inhibitory effects. Among them, compound <b>8g</b> (IC₅₀ = 0.62 ± 0.16 μM) showed significant inhibitory activity against rabbit muscle glycogen phosphorylase a (GPa). Its inhibition of glycogen degradation in HL-7702 cells was three times greater than that of <b>PSN-357</b>. Molecular docking studies revealed that the binding conformation of compound <b>8g</b> with PYGL allowed the benzoxazinone moiety to form stable hydrogen-bond networks and hydrophobic interactions, which may explain its excellent activity.