Synthesis, in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors. Issue 14 (15th July 2020)

• Record Type: Journal Article
• Authors: Miao, Guang-xin; Wang, You-de; Yan, Zhi-wei; Zhang, Li-ying
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 14(2020)
• Publication Date: 2020-07-15
• Subjects: Diabetes -- Glycogen phosphorylase inhibitors -- Biological activity -- ADME -- Blood glucose; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127117
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.