The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: lead optimization

Bioorg Med Chem Lett. 2014 Mar 15;24(6):1466-71. doi: 10.1016/j.bmcl.2014.02.011. Epub 2014 Feb 15.

Abstract

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.

Keywords: JAK2; Kinase partition index; Kinase selectivity; Kinases; Ligand binding affinity; Molecular modeling; Water interaction.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Animals
  • Binding Sites
  • Drug Evaluation, Preclinical
  • Half-Life
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Molecular Dynamics Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Structure, Tertiary
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics

Substances

  • Protein Kinase Inhibitors
  • Pyridones
  • Sulfonamides
  • Adenosine Triphosphate
  • Janus Kinase 2