Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one Derivatives as Novel JAK Inhibitors

Bioorg Med Chem. 2015 Aug 1;23(15):4846-59. doi: 10.1016/j.bmc.2015.05.028. Epub 2015 May 23.

Abstract

Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50=1.1 nM, 1.5 nM, respectively) with favorable metabolic stability.

Keywords: Autoimmune diseases; IL-2; Immunomodulator; Janus kinase inhibitor; Organ transplant rejection.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP3A / metabolism
  • 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
  • Male
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Pyridines / chemistry
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / pharmacology
  • Pyrroles / chemistry
  • Rats
  • Rats, Inbred Lew
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / metabolism
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyridines
  • Pyridones
  • Pyrroles
  • Cytochrome P-450 CYP3A
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3
  • pyrrolo(2, 3-b)pyridine