Abstract
A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
MeSH terms
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Alanine / analogs & derivatives*
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Alanine / chemical synthesis
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Alanine / pharmacokinetics
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Alanine / pharmacology
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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 Line, Tumor
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Drug Screening Assays, Antitumor
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Transplantation
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Prodrugs / chemical synthesis
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
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Triazines / chemical synthesis*
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Triazines / pharmacokinetics
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Triazines / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Substances
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Angiogenesis Inhibitors
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Prodrugs
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Pyrroles
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Triazines
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brivanib
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Vascular Endothelial Growth Factor Receptor-2
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Alanine