Discovery and Activity Evaluation of Novel Dibenzoxazepinone Derivatives as Glycogen Phosphorylase Inhibitors.

Inhibition of glycogen phosphorylases (GP) has been regarded as a therapeutic strategy for blood glucose control in diabetes. In this study, a series of novel dibenzoxazepinone derivatives was synthesized. The in vitro activity screening results indicated that compound Id most significantly inhibited glycogen phosphorylase (GP) activity, with an IC50 of 266 ± 1 nM, which was superior to the positive control drug PSN-357, a Phase II clinical GP inhibitor from Japan's OSI Corporation. In vivo experiments showed that Id could significantly reduce blood glucose levels in adrenaline-induced acute hyperglycemic mice and high-fat-diet-induced obese and diabetic (DIO) mice.