Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

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• 作者：Brian L. Hodous ; Stephanie D. Geuns-Meyer ; Paul E. Hughes ; Brian K. Albrecht ; Steve Bellon ; James Bready ; Sean Caenepeel ; Victor J. Cee ; Stuart C. Chaffee ; Angela Coxon ; Maurice Emery ; Jenne Fretland
• 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：611 - 626
• 全文大小：455K
• 年卷期：v.50,no.4(February 22, 2007)
• ISSN：1520-4804

文摘

Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth andsurvival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endotheliumand is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibitingTie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitorswith selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis.Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designedon the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Leadoptimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases,good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.