Abstract
High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC(50)=ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.
MeSH terms
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Alzheimer Disease / drug therapy*
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Amides / chemical synthesis
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Amides / therapeutic use*
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CDC2-CDC28 Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 5
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Drug Evaluation, Preclinical
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Molecular Structure
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Nerve Tissue Proteins / antagonists & inhibitors*
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / therapeutic use*
Substances
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Amides
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N-(5-isopropyl-thiazol-2-yl)isobutyramide
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Nerve Tissue Proteins
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TPPP protein, human
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Thiazoles
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2-aminothiazole
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Cyclin-Dependent Kinase 5
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CDC2-CDC28 Kinases
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases