Abstract
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
MeSH terms
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Alzheimer Disease / drug therapy*
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Animals
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Binding Sites
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Caco-2 Cells
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Crystallography, X-Ray
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Cyclin E / antagonists & inhibitors
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Cyclin E / metabolism
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinase 5 / antagonists & inhibitors
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Cyclin-Dependent Kinase 5 / metabolism*
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Drug Design
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / pharmacology
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / metabolism*
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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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Structure-Activity Relationship
Substances
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Cyclin E
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Imidazoles
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Nerve Tissue Proteins
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Protein Kinase Inhibitors
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TPPP protein, human
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4-aminoimidazole
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Cyclin-Dependent Kinase 5
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Cyclin-Dependent Kinase 2