Abstract
A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.
MeSH terms
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Administration, Oral
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Animals
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Checkpoint Kinase 1
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Cyanides / chemistry
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Hydrogen / chemistry*
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Indenes / chemistry
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Inhibitory Concentration 50
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Mice
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Molecular Structure
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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 / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinases / metabolism*
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Pyrazoles / administration & dosage
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology*
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Pyridines / chemistry*
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Rats
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Structure-Activity Relationship
Substances
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Cyanides
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Indenes
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridines
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pyrazole
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indene
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Hydrogen
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Protein Kinases
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Chek1 protein, rat
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pyridine