Identification of azabenzimidazoles as potent JAK1 selective inhibitors

Bioorg Med Chem Lett. 2016 Jan 1;26(1):60-7. doi: 10.1016/j.bmcl.2015.11.031. Epub 2015 Nov 12.

Abstract

We have identified a class of azabenzimidazoles as potent and selective JAK1 inhibitors. Investigations into the SAR are presented along with the structural features required to achieve selectivity for JAK1 versus other JAK family members. An example from the series demonstrated highly selective inhibition of JAK1 versus JAK2 and JAK3, along with inhibition of pSTAT3 in vivo, enabling it to serve as a JAK1 selective tool compound to further probe the biology of JAK1 selective inhibitors.

Keywords: Azabenzimidazoles; JAK selectivity; JAK1; JAK1 inhibitors.

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • STAT3 Transcription Factor
  • Janus Kinase 1