Discovery and Evaluation of 2-Anilino-5-aryloxazoles as a Novel Class of VEGFR2 Kinase Inhibitors

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. O...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-03, Vol.48 (5), p.1610-1619
Main Authors: Harris, Philip A, Cheung, Mui, Hunter, Robert N, Brown, Matthew L, Veal, James M, Nolte, Robert T, Wang, Liping, Liu, Wendy, Crosby, Renae M, Johnson, Jennifer H, Epperly, Andrea H, Kumar, Rakesh, Luttrell, Deirdre K, Stafford, Jeffrey A
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Angiogenesis Inhibitors - chemical synthesis
Angiogenesis Inhibitors - pharmacokinetics
Angiogenesis Inhibitors - pharmacology
Aniline Compounds - chemical synthesis
Aniline Compounds - pharmacokinetics
Aniline Compounds - pharmacology
Animals
Antineoplastic agents
Binding Sites
Biological and medical sciences
Cell Proliferation - drug effects
Cells, Cultured
Crystallography, X-Ray
Dogs
General aspects
Humans
Ligands
Male
Medical sciences
Mice
Models, Molecular
Oxazoles - chemical synthesis
Oxazoles - pharmacokinetics
Oxazoles - pharmacology
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Solubility
Structure-Activity Relationship
Umbilical Veins - cytology
Vascular Endothelial Growth Factor A - pharmacology
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 - chemistry
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049538w