Abstract
During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.
MeSH terms
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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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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Area Under Curve
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Computer Simulation
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Female
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HT29 Cells
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Humans
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Indicators and Reagents
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Male
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Mice
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Models, Molecular
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Neoplasm Transplantation
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology*
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RNA / biosynthesis
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RNA / genetics
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Receptor, TIE-2 / antagonists & inhibitors*
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacology*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Indicators and Reagents
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Pyrimidines
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RNA
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Urea
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Receptor, TIE-2
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Vascular Endothelial Growth Factor Receptor-2