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

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.

Citation

Zhiqin Ji, Asma A Ahmed, Daniel H Albert, Jennifer J Bouska, Peter F Bousquet, George A Cunha, Gilbert Diaz, Keith B Glaser, Jun Guo, Christopher M Harris, Junling Li, Patrick A Marcotte, Maria D Moskey, Tetsuro Oie, Lori Pease, Nirupama B Soni, Kent D Stewart, Steven K Davidsen, Michael R Michaelides. 3-amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases. Journal of medicinal chemistry. 2008 Mar 13;51(5):1231-41

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PMID: 18260617

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