Abstract
The design of a novel series of cyclin-dependent kinase (CDK) inhibitors containing a macrocyclic quinoxaline-2-one is reported. Structure-based drug design and optimization from the starting point of diarylurea 2, which we previously reported as a moderate CDK1,2,4,6 inhibitor [J. Biol.Chem.2001, 276, 27548], led to the discovery of potent CDK1,2,4,6 inhibitor that were suitable for iv administration for in vivo study.
MeSH terms
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Animals
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Binding Sites
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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2-CDC28 Kinases / antagonists & inhibitors*
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Crystallography, X-Ray
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors
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Drug Design
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Humans
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Hydrogen Bonding
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Inhibitory Concentration 50
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / pharmacology
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Molecular Structure
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Quinoxalines / chemical synthesis*
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Quinoxalines / pharmacology*
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Structure-Activity Relationship
Substances
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Macrocyclic Compounds
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Quinoxalines
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CDC2 Protein Kinase
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CDC2-CDC28 Kinases
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6