Design of novel quinazoline derivatives and related analogues as potent and selective ALK5 inhibitors

Bioorg Med Chem Lett. 2009 Apr 15;19(8):2277-81. doi: 10.1016/j.bmcl.2009.02.087. Epub 2009 Feb 26.

Abstract

Starting from quinazoline 3a, we designed potent and selective ALK5 inhibitors over p38MAP kinase from a rational drug design approach based on co-crystal structures in the human ALK5 kinase domain. The quinazoline 3d exhibited also in vivo activity in an acute rat model of DMN-induced liver fibrosis when administered orally at 5mg/kg (bid).

Publication types

  • Comparative Study

MeSH terms

  • Activin Receptors / antagonists & inhibitors*
  • Activin Receptors / metabolism
  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Protein Binding
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Quinazolines / administration & dosage
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacology
  • Rats
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / metabolism

Substances

  • Protein Kinase Inhibitors
  • Quinazolines
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Activin Receptors
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, rat

Associated data

  • PDB/1JYJE
  • PDB/1SWZE