Abstract
A novel class of furo[2,3-d]pyrimidines has been discovered as potent dual inhibitors of Tie-2 and VEGFR2 receptor tyrosine kinases (TK) and a diarylurea moiety at 5-position shows remarkably enhanced activity against both enzymes. One of the most active compounds, 4-amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (7k) is <3 nM on both TK receptors and the activity is rationalized based on the X-ray crystal structure.
MeSH terms
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3T3 Cells
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Animals
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Binding Sites
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Cell Division / drug effects
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Cells, Cultured
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Crystallography, X-Ray
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Humans
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Mice
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Models, Molecular
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Protein Conformation
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology*
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Receptor, TIE-2 / antagonists & inhibitors*
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Receptor, TIE-2 / chemistry
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Structure-Activity Relationship
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Transfection
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Umbilical Veins
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Urea / analogs & derivatives
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Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-1 / chemistry
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / chemistry
Substances
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Pyrimidines
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Urea
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Receptor, TIE-2
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2