Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain

J Med Chem. 2003 Sep 11;46(19):3953-6. doi: 10.1021/jm0205705.

Abstract

Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.

MeSH terms

  • 3T3 Cells
  • Adenosine Triphosphate / metabolism
  • Animals
  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / metabolism
  • Benzene Derivatives / pharmacology*
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mink
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Models, Molecular
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology*
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / metabolism
  • Spodoptera
  • Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Benzene Derivatives
  • Enzyme Inhibitors
  • Pyrazoles
  • Receptors, Transforming Growth Factor beta
  • Adenosine Triphosphate
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases