Alkynylpyrimidine Amide Derivatives as Potent, Selective, and Orally Active Inhibitors of Tie-2 Kinase
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- 作者：Victor J. Cee ; Brian K. Albrecht ; Stephanie Geuns-Meyer ; Paul Hughes ; Steve Bellon ; James Bready ; Sean Caenepeel ; Stuart C. Chaffee ; Angela Coxon ; Maurice Emery ; Jenne Fretland ; Paul Gallant ; Yan Gu
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：February 22, 2007
- 年：2007
- 卷：50
- 期：4
- 页码：627 - 640
- 全文大小：257K
- 年卷期：v.50,no.4(February 22, 2007)
- ISSN：1520-4804
文摘
The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer,and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulateblood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cellsand is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agentssuch as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugateshas been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering withthe Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Hereinwe describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally availableATP-competitive inhibitors of Tie-2 autophosphorylation.