Discovery and evaluation of novel benzazepinone derivatives as glycogen phosphorylase inhibitors with potent activity

Future Med Chem. 2021 May;13(10):897-909. doi: 10.4155/fmc-2020-0352. Epub 2021 Apr 28.

Abstract

Glycogen phosphorylase (GP) is a key enzyme of glycogen catabolism, so it is significant to discover a new GP inhibitor. A series of benzazepinone derivatives were discovered as GP inhibitors with potent activity. Among these derivatives, compound 5d showed significant potential against rabbit muscle GPa (IC50 = 0.25 ± 0.05 μM) and cellular efficacy. The in vivo study revealed that 5d significantly inhibited increases in fasting blood glucose level in two kinds of hyperglycemic mice models. The possible binding mode of compound 5d was explored based on molecular docking simulations. These results indicated that derivatives with benzazepinone were potential chemical entities against hyperglycemia.

Keywords: benzazepinone derivatives; biological activity; glycogen phosphorylase inhibitors; molecular docking; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / chemical synthesis
  • Benzazepines / chemistry
  • Benzazepines / pharmacology*
  • Blood Glucose / drug effects
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Phosphorylase / antagonists & inhibitors*
  • Glycogen Phosphorylase / metabolism
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Rabbits

Substances

  • Benzazepines
  • Blood Glucose
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Glycogen Phosphorylase