2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6529-33. doi: 10.1016/j.bmcl.2009.10.053. Epub 2009 Oct 24.

Abstract

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

MeSH terms

  • Crystallography, X-Ray
  • Drug Discovery
  • Janus Kinase 2 / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Signal Transduction / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Janus Kinase 2