Novel and potent transforming growth factor beta type I receptor kinase domain inhibitor: 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3585-8. doi: 10.1016/j.bmcl.2004.04.065.

Abstract

A novel series of 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines was synthesized and their TbetaR-1 inhibitory, p38 MAPK inhibitory, and TbetaR-1-dependent cellular activity were evaluated. Compound 5a was found to be a highly potent in the enzyme assay and TbetaR-1-dependent cellular assays. In addition, dimer (4g), with a urea linker, shows a similar enzyme and cellular activity despite a bulky substitution.

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • Cells, Cultured
  • Dimerization
  • Humans
  • Inhibitory Concentration 50
  • Protein Serine-Threonine Kinases
  • Protein Structure, Tertiary
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology
  • Quinolines / chemical synthesis
  • Quinolines / pharmacology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Urea / chemistry
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Pyrazoles
  • Pyrroles
  • Quinolines
  • Receptors, Transforming Growth Factor beta
  • Urea
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I