Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase

MEDI 372

Karina Romero, romerok@amgen.com1, Stephanie Geuns-Meyer1, Paul Hughes1, Annette Bak1, Steve Bellon1, James Bready1, Sean Caenepeel1, Victor J Cee2, Stuart C Chaffee1, Angela Coxon1, Holly L. Deak1, Maurice Emery1, Jenne Fretland1, Paul Gallant1, Yan Gu1, Brian L Hodous1, Doug Hoffman1, Rebecca E Johnson1, Richard Kendall1, Joseph L Kim1, Jasmine Lin1, Alexander M Long1, Michael Morrison1, Hanh N Nguyen1, Philip R Olivieri II1, Vinod F Patel1, Anthony Polverino1, David Powers1, Paul Rose1, Mary K Stanton1, Ling Wang1, and Huilin Zhao1. (1) Amgen, Inc, 1 Kendall Square, Bldg 1000, Cambridge, MA 02139, (2) Department of Medicinal Chemistry, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320
Inhibition of angiogenesis is a promising and clinically established approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for developmental angiogenesis and vessel maturation. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves targeting the ATP binding site of the Tie-2 kinase domain. Potent, orally bioavailable, and selective kinase inhibitors are essential in assessing the therapeutic utility of this approach. Toward this end, we describe the development of pyridyl-pyrimidine benzimidazole derivatives as ATP-competitive inhibitors of Tie-2 autophosphorylation.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007