Abstract
The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
MeSH terms
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Adenosine Triphosphate / metabolism
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Alkynes / chemical synthesis*
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Alkynes / pharmacokinetics
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Alkynes / pharmacology
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Amides / chemical synthesis*
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Amides / pharmacokinetics
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Amides / 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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Binding Sites
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Blood Proteins / metabolism
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Cell Line
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Female
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Humans
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In Vitro Techniques
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Lung / drug effects
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Lung / enzymology
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Male
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology
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Phosphorylation
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Protein Binding
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / 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 / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Alkynes
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Amides
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Angiogenesis Inhibitors
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Blood Proteins
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Pyrimidines
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Adenosine Triphosphate
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Receptor, TIE-2