Abstract
A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR-2, EGFR, AKT1, ALK1, and ABL1. The anti-angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR-2 and ABL1 and higher anti-angiogenic activity compared with Pazopanib, the reference standard. These two compounds (P2d and P2e) could be used as novel lead compounds for further development of anticancer agents.
Keywords:
anti-angiogenesis; antitumor agent; pazopanib derivatives; synthesis.
© 2013 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Aorta / cytology
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Aorta / drug effects
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Aorta / metabolism
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Cell Survival / drug effects
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Cells, Cultured
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Drug Design*
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Enzyme Activation / drug effects
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Indazoles / chemical synthesis*
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Indazoles / chemistry
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Indazoles / pharmacology*
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Male
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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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Proto-Oncogene Proteins c-abl / antagonists & inhibitors
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Proto-Oncogene Proteins c-abl / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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4-((4-((2,3-dimethyl-2H-indazole-6-yl)(methyl)amino)pyrimidin-2-yl)amino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide
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4-((4-((2,3-dimethyl-2H-indazole-6-yl)(methyl)amino)pyrimidin-2-yl)amino)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide
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Antineoplastic Agents
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Indazoles
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Protein Kinase Inhibitors
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Pyrimidines
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Sulfonamides
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pazopanib
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Vascular Endothelial Growth Factor Receptor-2
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Proto-Oncogene Proteins c-abl