Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines

Bioorg Med Chem Lett. 2014 Nov 1;24(21):4969-75. doi: 10.1016/j.bmcl.2014.09.031. Epub 2014 Sep 21.

Abstract

The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.

Keywords: Intramolecular hydrogen bond; JAK; Janus kinase; Kinase inhibitors; Scaffold hopping; Structure based drug design.

Publication types

  • Comparative Study

MeSH terms

  • Drug Design
  • Humans
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Phosphorylation
  • Piperidines / pharmacology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / chemistry*
  • Pyrimidines / pharmacology
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Structure-Activity Relationship

Substances

  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrimidines
  • Pyrroles
  • tofacitinib
  • Janus Kinase 3