9H-Carbazole-1-carboxamides as potent and selective JAK2 inhibitors

Bioorg Med Chem Lett. 2015 Jul 15;25(14):2809-12. doi: 10.1016/j.bmcl.2015.04.101. Epub 2015 May 11.

Abstract

The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.

Keywords: JAK; JAK family selectivity; JAK1; JAK2; JAK3; Myeloproliferative disorders; Myeloproliferative neoplasms; TYK2.

MeSH terms

  • Amides / chemistry*
  • Amides / metabolism
  • Amides / pharmacology
  • Binding Sites
  • Carbazoles / chemistry
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Janus Kinase 3 / antagonists & inhibitors
  • Janus Kinase 3 / metabolism
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Amides
  • Carbazoles
  • Protein Kinase Inhibitors
  • carbazole
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3