3-Amino-benzo[d]isoxazoles as Novel Multitargeted Inhibitors of Receptor Tyrosine Kinases
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- 作者：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 ; Mar
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：March 13, 2008
- 年：2008
- 卷：51
- 期：5
- 页码：1231 - 1241
- 全文大小：535K
- 年卷期：v.51,no.5(March 13, 2008)
- ISSN：1520-4804
文摘
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 ED50 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.