Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase

• Published in: Journal of medicinal chemistry 2011-10, Vol.54 (20), p.7066-7083
• Main Authors: Guagnano, Vito, Furet, Pascal, Spanka, Carsten, Bordas, Vincent, Le Douget, Mickaël, Stamm, Christelle, Brueggen, Josef, Jensen, Michael R, Schnell, Christian, Schmid, Herbert, Wartmann, Markus, Berghausen, Joerg, Drueckes, Peter, Zimmerlin, Alfred, Bussiere, Dirksen, Murray, Jeremy, Graus Porta, Diana
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Nude; Models, Molecular; Neoplasm Transplantation; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Rats; Rats, Wistar; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Structure-Activity Relationship; Transplantation, Heterologous; Urinary Bladder Neoplasms
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2006222

A novel series of N-aryl-N′-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.