Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7627-33. doi: 10.1016/j.bmcl.2012.10.008. Epub 2012 Oct 11.

Abstract

Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Imidazoles / chemistry
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Male
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrroles / administration & dosage
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrroles
  • Janus Kinase 1
  • Janus Kinase 2