Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome

Bioorg Med Chem Lett. 2013 May 1;23(9):2793-800. doi: 10.1016/j.bmcl.2013.02.012. Epub 2013 Feb 13.

Abstract

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Hydrophobic and Hydrophilic Interactions
  • Indazoles / chemistry
  • 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 Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazines / metabolism
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Protein Kinase Inhibitors
  • Pyrazines
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3