Abstract
Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC(50) of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides / chemical synthesis
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Benzamides / chemistry
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Benzamides / pharmacology
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Benzamides / therapeutic use*
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Cells, Cultured
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / enzymology
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Drug Discovery*
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Enzyme Activation / drug effects
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Glucokinase / metabolism*
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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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Hypoglycemic Agents / therapeutic use*
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Mice
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Mice, Inbred C57BL
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Mice, Obese
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Molecular Structure
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Phenethylamines / chemical synthesis
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Phenethylamines / chemistry
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Phenethylamines / pharmacology
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyridines / therapeutic use*
Substances
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Benzamides
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Hypoglycemic Agents
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Phenethylamines
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Pyridines
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YH-GKA
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benzamide
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Glucokinase