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

• Published in: Journal of medicinal chemistry Vol. 50; no. 4; pp. 611 - 626
• Main Authors: Hodous, Brian L, Geuns-Meyer, Stephanie D, Hughes, Paul E, Albrecht, Brian K, Bellon, Steve, Bready, James, Caenepeel, Sean, Cee, Victor J, Chaffee, Stuart C, Coxon, Angela, Emery, Maurice, Fretland, Jenne, Gallant, Paul, Gu, Yan, Hoffman, Doug, Johnson, Rebecca E, Kendall, Richard, Kim, Joseph L, Long, Alexander M, Morrison, Michael, Olivieri, Philip R, Patel, Vinod F, Polverino, Anthony, Rose, Paul, Tempest, Paul, Wang, Ling, Whittington, Douglas A, Zhao, Huilin
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 22-02-2007
• Subjects: Administration, Oral; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Animals; Benzamides - chemical synthesis; Benzamides - pharmacokinetics; Benzamides - pharmacology; Binding Sites; Biological and medical sciences; Blood Proteins - metabolism; Crystallography, X-Ray; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Male; Medical sciences; Mice; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Phosphorylation; Protein Binding; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, TIE-2 - antagonists & inhibitors; Receptor, TIE-2 - chemistry; Receptor, TIE-2 - metabolism; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - pharmacokinetics; Triazines - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Intravenous administration; Rat; Selectivity; Pyridine derivatives; Angiogenesis; Signal transduction; Structure activity relation; Neovascularization; Protein-tyrosine kinase; Enzyme; Transferases; Rodentia; Oral administration; Bioavailability; In vitro; Diamine; In vivo; Vertebrata; Mammalia; Animal; Organic fluorine compounds; Triazine derivatives; Benzamide derivatives; Carboxamide; Inhibitor; Pharmacokinetics; Tie 2 receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061107l

Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with 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 designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization 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.