Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases

J Med Chem. 2008 Aug 14;51(15):4672-84. doi: 10.1021/jm800343j. Epub 2008 Jul 23.


The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.

MeSH terms

  • Amines / chemistry*
  • Animals
  • Cell Line
  • Humans
  • Male
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemistry*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptor, trkA / antagonists & inhibitors*
  • Receptor, trkA / chemistry
  • Receptor, trkA / metabolism
  • Structure-Activity Relationship


  • 5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
  • Amines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Receptor, trkA