Abstract
Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).
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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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Benzoxazoles / chemical synthesis*
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Benzoxazoles / pharmacokinetics
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Benzoxazoles / pharmacology
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Biological Availability
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Capillary Permeability / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Cornea / blood supply
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Cornea / drug effects
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Crystallography, X-Ray
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Drug Design
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Female
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Humans
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Male
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Mice
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Mice, Nude
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Models, Molecular
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Molecular Structure
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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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Structure-Activity Relationship
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Umbilical Veins / cytology
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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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4-((2-((4-chloro-3-(((1-methyl-2-pyrrolidinyl)methyl)oxy)phenyl)amino)-1,3-benzoxazol-5-yl)oxy)-N-methyl-2-pyridinecarboxamide
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Angiogenesis Inhibitors
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Benzimidazoles
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Benzoxazoles
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Pyridines
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Vascular Endothelial Growth Factor Receptor-2