Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors

J Med Chem. 2004 Aug 26;47(18):4494-506. doi: 10.1021/jm0400247.

Abstract

Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Inhibitory Concentration 50
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / pharmacology*
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Serine-Threonine Kinases
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Naphthyridines
  • Pyrazoles
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human

Associated data

  • PDB/1VJY