Abstract
Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.
MeSH terms
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Administration, Oral
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / pharmacokinetics
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Angiogenesis Inhibitors / pharmacology
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Animals
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Cell Proliferation / drug effects
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Cells, Cultured
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Drug Design*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Hemangiosarcoma / blood supply
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Hemangiosarcoma / drug therapy
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Hemangiosarcoma / enzymology
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Humans
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Melanoma, Experimental / blood
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Melanoma, Experimental / blood supply
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Melanoma, Experimental / drug therapy*
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Melanoma, Experimental / enzymology
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Molecular Structure
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Neovascularization, Pathologic
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Oximes / chemical synthesis*
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Oximes / pharmacokinetics
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Oximes / pharmacology*
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Rats
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Receptor, TIE-2 / antagonists & inhibitors*
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Receptor, TIE-2 / metabolism
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Structure-Activity Relationship
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Umbilical Veins
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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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Angiogenesis Inhibitors
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Oximes
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Protein Kinase Inhibitors
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Receptor, TIE-2
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Vascular Endothelial Growth Factor Receptor-2