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

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journal contribution
posted on 10.03.2005, 00:00 by Philip A. Harris, Mui Cheung, Robert N. Hunter, Matthew L. Brown, James M. Veal, Robert T. Nolte, Liping Wang, Wendy Liu, Renae M. Crosby, Jennifer H. Johnson, Andrea H. Epperly, Rakesh Kumar, Deirdre K. Luttrell, Jeffrey A. Stafford
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.