Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity versus transforming growth factor-beta type II receptor kinase and mixed lineage kinase-7

J Med Chem. 2006 Mar 23;49(6):2138-42. doi: 10.1021/jm058209g.

Abstract

Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Cells, Cultured
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Mice
  • Mice, Nude
  • Mink
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Structure, Tertiary
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • 6-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo(1,2-b)pyrazol-3-yl)-1H-benzoimidazole
  • Benzimidazoles
  • Pyrazoles
  • Pyrroles
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Receptor, Transforming Growth Factor-beta Type I