Abstract
A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenosine Triphosphate / chemistry
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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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Aniline Compounds / chemical synthesis*
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Aniline Compounds / pharmacokinetics
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Aniline Compounds / pharmacology
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Animals
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Binding Sites
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Cell Proliferation / drug effects
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Cells, Cultured
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Crystallography, X-Ray
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Dogs
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Humans
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Ligands
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Male
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Mice
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Models, Molecular
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Oxazoles / chemical synthesis*
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Oxazoles / pharmacokinetics
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Oxazoles / pharmacology
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Rats
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Rats, Sprague-Dawley
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Solubility
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Structure-Activity Relationship
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Umbilical Veins / cytology
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / chemistry
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Aniline Compounds
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Ligands
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N,5-diphenyl-1,3-oxazol-2-amine
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Oxazoles
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Vascular Endothelial Growth Factor A
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Adenosine Triphosphate
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Vascular Endothelial Growth Factor Receptor-2