Abstract
In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Amination
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Aurora Kinase B
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Aurora Kinases
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemistry*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrazoles / chemistry*
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Structure-Activity Relationship
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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pyrazole
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Vascular Endothelial Growth Factor Receptor-2
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AURKB protein, human
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Aurkb protein, mouse
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases