Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors

Bioorg Med Chem. 2018 Sep 15;26(17):4774-4786. doi: 10.1016/j.bmc.2018.04.005. Epub 2018 Apr 4.

Abstract

Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 μM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.

Keywords: 1H-Pyrazolo[3,4-d]pyrimidin-4-amino derivatives; Covalent JAK3 inhibitors; Janus kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamide / chemistry
  • Animals
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Cell Proliferation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Interleukin-2 / pharmacology
  • Janus Kinase 3 / antagonists & inhibitors*
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Proton Magnetic Resonance Spectroscopy
  • Pyrazoles / chemistry*
  • Pyrimidines / chemistry*
  • Rats
  • Spectrometry, Mass, Electrospray Ionization
  • T-Lymphocytes / drug effects

Substances

  • Interleukin-2
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Acrylamide
  • JAK3 protein, human
  • Janus Kinase 3