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Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors.

Harris PA, Cheung M, Hunter RN, Brown ML, Veal JM, Nolte RT, Wang L, Liu W, Crosby RM, Johnson JH, Epperly AH, Kumar R, Luttrell DK, Stafford JA
J Med Chem 48 1610-9 (2005)
Cited: 61 times
EuropePMC logo PMID: 15743202

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.

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  6. DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular. Buchanan CM, Shih JH, Astin JW, Rewcastle GW, Flanagan JU, Crosier PS, Shepherd PR. Clin Sci (Lond) 122 449-457 (2012)
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  13. Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study. Salem MG, El-Maaty DMA, El-Deen YIM, Elesawy BH, Askary AE, Saleh A, Saied EM, Behery ME. Molecules 27 4898 (2022)
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  16. de novo design and synthesis of N-benzylanilines as new candidates for VEGFR tyrosine kinase inhibitors. Uno M, Ban HS, Nabeyama W, Nakamura H. Org Biomol Chem 6 979-981 (2008)
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  21. Evolution of a New Class of VEGFR-2 Inhibitors from Scaffold Morphing and Redesign. Mainolfi N, Karki R, Liu F, Anderson K. ACS Med Chem Lett 7 363-367 (2016)
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