Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5)

J Med Chem. 2002 Feb 28;45(5):999-1001. doi: 10.1021/jm010493y.

Abstract

Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fibronectins / biosynthesis
  • Fibronectins / genetics
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger / biosynthesis
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Smad3 Protein
  • Structure-Activity Relationship
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Fibronectins
  • Imidazoles
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • SMAD3 protein, human
  • Smad3 Protein
  • Trans-Activators
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human