Abstract
A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.
MeSH terms
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Administration, Oral
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Animals
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Crystallography, X-Ray
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Diabetes Mellitus, Experimental / drug therapy
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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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Glycogen Phosphorylase, Liver Form / antagonists & inhibitors*
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Glycogen Phosphorylase, Liver Form / chemistry
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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 / therapeutic use
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Liver / enzymology*
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Mice
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Mice, Obese
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Models, Molecular
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Molecular Structure
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Stereoisomerism
Substances
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5-chloro-N-(4-(1,2-dihydroxyethyl)phenyl)-1H-indole-2-carboxamide
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Enzyme Inhibitors
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Hypoglycemic Agents
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Indoles
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Glycogen Phosphorylase, Liver Form