Abstract
Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was observed with compound 37 against L2987 human lung carcinoma xenografts in athymic mice.
MeSH terms
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Animals
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Cell Line, Tumor
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Cyclopropanes / chemical synthesis
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Cyclopropanes / chemistry*
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Cyclopropanes / pharmacology*
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Cytochrome P-450 Enzyme Inhibitors
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Humans
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Lung Neoplasms / drug therapy
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Mice
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Mice, Nude
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Oxadiazoles / chemical synthesis
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology
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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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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Structure-Activity Relationship
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Triazines / chemical synthesis
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Triazines / chemistry*
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Triazines / pharmacology*
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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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Cyclopropanes
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Cytochrome P-450 Enzyme Inhibitors
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Oxadiazoles
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Protein Kinase Inhibitors
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Pyrroles
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Triazines
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Vascular Endothelial Growth Factor Receptor-2