Abstract
A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation.
MeSH terms
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Administration, Oral
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Amides / chemistry*
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Biological Availability
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Carbamates / chemistry*
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Carbazoles / chemical synthesis
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Carbazoles / chemistry
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Carbazoles / pharmacology*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Indazoles / chemical synthesis
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Indazoles / chemistry
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Indazoles / pharmacology*
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Mice
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Mice, Nude
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Molecular Structure
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Rats
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Receptor, TIE-2 / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Urea / chemistry*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Substances
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Amides
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Antineoplastic Agents
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Carbamates
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Carbazoles
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Enzyme Inhibitors
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Indazoles
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Urea
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Receptor, TIE-2
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Vascular Endothelial Growth Factor Receptor-2