Abstract
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
MeSH terms
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Administration, Oral
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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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Benzamides / chemical synthesis*
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Benzamides / pharmacokinetics
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Benzamides / pharmacology
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Binding Sites
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Blood Proteins / metabolism
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Crystallography, X-Ray
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Female
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Humans
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Injections, Intraperitoneal
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Injections, Intravenous
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Male
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Mice
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Models, Molecular
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Molecular Structure
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Phosphorylation
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Protein Binding
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, TIE-2 / antagonists & inhibitors*
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Receptor, TIE-2 / chemistry
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Receptor, TIE-2 / metabolism
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Structure-Activity Relationship
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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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Benzamides
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Blood Proteins
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N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-yloxy)benzamide
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Pyridines
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Triazines
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Receptor, TIE-2
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Vascular Endothelial Growth Factor Receptor-2