Abstract
In the course of searching for new p38α MAP kinase inhibitors, we found that the regioisomeric switch from 3-(4-fluorophenyl)-4-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine to 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine led to an almost complete loss of p38α inhibition, but they showed activity against important cancer kinases. Among the tested derivatives, 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazol-5-amine (6a) exhibited the best activity, with IC(50) in the nanomolar range against Src, B-Raf wt, B-Raf V600E, EGFRs, and VEGFR-2, making it a good lead for novel anticancer programs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Enzyme Assays
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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Models, Molecular
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Mutation
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Neoplasms / enzymology*
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins B-raf / genetics
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Stereoisomerism
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Structure-Activity Relationship
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / genetics
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrazoles
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ErbB Receptors
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Vascular Endothelial Growth Factor Receptor-2
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src-Family Kinases
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Proto-Oncogene Proteins B-raf
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p38 Mitogen-Activated Protein Kinases