3-Amino benzo[d]isoxazoles as novel multitargeted receptor tyrosine kinase inhibitors

MEDI 114

Zhiqin Ji, zhiqin.ji@abbott.com1, Asma A. Ahmed2, Daniel H. Albert1, Jennifer J. Bouska1, Peter F. Bousquet2, George A. Cunha2, Keith B. Glaser1, Eric F. Johnson1, Jun Guo1, Junling Li1, Patrick A Marcotte1, Maria D. Moskey2, Lori J. Pease1, Nirupama B. Soni1, Kent D. Stewart1, Paul Tapang1, Melinda S. Yates1, Steven K. Davidsen1, and Michael R. Michaelides1. (1) Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, (2) Global Pharmaceutical Research and Development, Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605
Over-activation of receptor tyrosine kinases (RTKs) is associated with various human cancers. Interruption of RTK signaling pathways has proven to be a promising strategy in anticancer drug research. We have discovered that 3-amino benzo[d]isoxazoles potently inhibit KDR, FLT1, FLT3, FLT 4, CSF1R and cKIT with both enzymatic and cellular IC50 values below 100 nM. Selected compounds display promising pharmacokinetic profiles with high oral bioavailability. These compounds also exhibit excellent in vivo efficacy in blocking VEGF-mediated uterine edema and inhibiting the growth of human tumor xenografts (HT1080 ED75 < 20 mg/kg/day).
 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006