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

J Med Chem. 2011 Oct 27;54(20):7066-83. doi: 10.1021/jm2006222. Epub 2011 Sep 21.

Abstract

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.

MeSH terms

  • 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

Substances

  • 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Phenylurea Compounds
  • Pyrimidines
  • Receptors, Fibroblast Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 3