Abstract
A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC(50) values below 0.3nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics*
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Caco-2 Cells
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Checkpoint Kinase 1
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Chemistry, Pharmaceutical / methods*
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DNA Damage
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Drug Design
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Drug Screening Assays, Antitumor*
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Flow Cytometry
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Humans
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Inhibitory Concentration 50
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Mice
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Microsomes, Liver / metabolism
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics*
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Protein Kinases / chemistry*
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Protein Kinases / metabolism
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Rats
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Chek1 protein, rat