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J Med Chem. 2008 Mar 13;51(5):1231-41. doi: 10.1021/jm701096v. Epub 2008 Feb 9.

3-amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases.

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Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6100, USA.


A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.

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