Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4399-404. doi: 10.1016/j.bmcl.2015.09.020. Epub 2015 Sep 8.

Abstract

Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.

Keywords: 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines; Jak inhibitors; Jak selectivity; Tricyclic pyrrolopyrazines.

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Male
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • 6H-pyrrolo(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine
  • Protein Kinase Inhibitors
  • Pyrazines
  • Triazoles
  • JAK1 protein, human
  • Janus Kinase 1