Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors

Bioorg Med Chem Lett. 2010 Nov 1;20(21):6242-5. doi: 10.1016/j.bmcl.2010.08.100. Epub 2010 Sep 16.

Abstract

Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.

MeSH terms

  • Animals
  • Benzodioxoles / chemical synthesis*
  • Benzodioxoles / pharmacokinetics
  • Benzodioxoles / pharmacology*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Dogs
  • Female
  • Male
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Phosphorylation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Rats
  • Rats, Wistar
  • Receptor, EphB4 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Substrate Specificity
  • src-Family Kinases / antagonists & inhibitors

Substances

  • Benzodioxoles
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Receptor, EphB4
  • src-Family Kinases