Synthesis, in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors

  • Bioorg Med Chem Lett. 2020 Jul 15;30(14):127117. doi: 10.1016/j.bmcl.2020.127117.
Guang-Xin Miao  1 ,  You-de Wang  1 ,  Zhi-Wei Yan  1 ,  Li-Ying Zhang  2
Affiliations
  • 1. Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China.
  • 2. Key Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China. Electronic address: [email protected].
PMID: 32527535 DOI: 10.1016/j.bmcl.2020.127117
Abstract

A small set of indole-2-carboxamide derivatives identified from a high-throughput screening campaign has been described as a novel, potent, and glucose-sensitive inhibitors of glycogen Phosphorylase a (GPa). Among this series of compounds, compound 2 exhibited moderate GP inhibitory activity (IC50 = 0.29 μM), good cellular efficacy (IC50 = 3.24 μM for HepG2 cells and IC50 = 7.15 μM for isolated rat hepatocytes), together with good absorption, distribution, metabolism, and elimination (ADME) profiles. The in vivo animal study revealed that compound 2 significantly inhibited an increase of fasting blood glucose level in adrenaline-induced diabetic mice.

Keywords
ADME; Biological activity; Blood glucose; Diabetes; Glycogen phosphorylase inhibitors.