Abstract
The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50)<10nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters.
MeSH terms
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Administration, Oral
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Animals
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Aurora Kinase A
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Aurora Kinases
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Binding Sites
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Hydrogen Bonding
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Purines / chemical synthesis
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Purines / chemistry
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Purines / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Protein Kinase Inhibitors
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Purines
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Pyrimidines
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Aurka protein, rat
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Aurora Kinase A
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Aurora Kinases
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Protein Serine-Threonine Kinases
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Glycogen Synthase Kinase 3