Abstract
Design, synthesis and biological evaluation of the imidazopyridine analogs as novel GSK3β inhibitors for treatment of type 2 diabetes mellitus are described. Most of the analogs exhibited excellent inhibitory activities (IC50<44 nM) against glycogen synthase kinase 3β (GSK3β). The structure-activity relationship (SAR) of the imidazopyridine analogs and the binding mode of analog 23 in the catalytic domain of GSK3β, based on our X-ray crystallography study, are described. In particular, analog 28, which was selected as a potential drug candidate for treatment of type 2 diabetes mellitus, exhibited excellent GSK3β inhibition, pharmacokinetic profiles and blood glucose lowering effect in mouse.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Aminopyridines / chemical synthesis*
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Aminopyridines / pharmacokinetics
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Aminopyridines / therapeutic use
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Animals
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Binding Sites
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Blood Glucose / analysis
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Crystallography, X-Ray
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Diabetes Mellitus, Experimental / drug therapy
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Drug Design*
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / therapeutic use
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry*
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Imidazoles / pharmacokinetics
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Imidazoles / therapeutic use
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Male
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Mice
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Mice, Inbred ICR
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Microsomes / metabolism
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Protein Structure, Tertiary
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / therapeutic use
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Structure-Activity Relationship
Substances
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Aminopyridines
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Blood Glucose
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Hypoglycemic Agents
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Imidazoles
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Pyridines
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Glycogen Synthase Kinase 3