Abstract
We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma.
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / classification
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Antineoplastic Agents / metabolism
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Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / metabolism
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Caco-2 Cells
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 2 / metabolism
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Drug Design*
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / chemical synthesis
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Growth Inhibitors / classification
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Growth Inhibitors / metabolism
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Mice
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Mice, Nude
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / classification*
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Protein Kinase Inhibitors / metabolism
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Pyrazoles / chemistry*
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Pyrroles / chemistry*
Substances
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Growth Inhibitors
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Isoenzymes
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrroles
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CDK2 protein, human
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Cyclin-Dependent Kinase 2