Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4750-5. doi: 10.1016/j.bmcl.2012.05.067. Epub 2012 May 26.

Abstract

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.

MeSH terms

  • Amination
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Aurora Kinase B
  • Aurora Kinases
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrazoles / chemistry*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • pyrazole
  • Vascular Endothelial Growth Factor Receptor-2
  • AURKB protein, human
  • Aurkb protein, mouse
  • Aurora Kinase B
  • Aurora Kinases
  • Protein Serine-Threonine Kinases