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.
Copyright © 2020. Published by Elsevier Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / drug effects*
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Cell Proliferation / drug effects
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / metabolism
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Epinephrine
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Glycogen Phosphorylase / antagonists & inhibitors*
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Glycogen Phosphorylase / metabolism
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Hep G2 Cells
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Hepatocytes / drug effects
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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology*
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology*
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Mice
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Molecular Structure
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Rats
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Structure-Activity Relationship
Substances
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Blood Glucose
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Enzyme Inhibitors
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Hypoglycemic Agents
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Indoles
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Glycogen Phosphorylase
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Epinephrine