Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1

Bioorg Med Chem Lett. 2013 Jun 15;23(12):3592-8. doi: 10.1016/j.bmcl.2013.04.018. Epub 2013 Apr 17.

Abstract

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Publication types

  • Letter

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / chemistry
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / chemistry
  • Kinetics
  • Models, Molecular
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Rats

Substances

  • Pyridines
  • Pyrroles
  • Janus Kinase 1
  • Janus Kinase 2