Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3581-4. doi: 10.1016/j.bmcl.2004.04.007.


We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • Activin Receptors, Type I / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cells, Cultured
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Protein Serine-Threonine Kinases
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Quinolines / chemistry
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Enzyme Inhibitors
  • Pyrazoles
  • Quinolines
  • Receptors, Transforming Growth Factor beta
  • Adenosine Triphosphate
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I