Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors

Bioorg Med Chem Lett. 2013 May 1;23(9):2522-6. doi: 10.1016/j.bmcl.2013.03.015. Epub 2013 Mar 14.

Abstract

We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Drug Evaluation, Preclinical
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / metabolism
  • Molecular Docking Simulation
  • Phenyl Ethers / chemical synthesis
  • Phenyl Ethers / chemistry*
  • Phenyl Ethers / metabolism
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Pyridazines / chemistry*
  • Pyrroles / chemistry*
  • Structure-Activity Relationship

Substances

  • Phenyl Ethers
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Pyridazines
  • Pyrroles
  • Pyrrolopyridazine
  • Janus Kinase 3