Structure-based design and synthesis of pyrimidine-4,6-diamine derivatives as Janus kinase 3 inhibitors

Bioorg Med Chem. 2019 Apr 15;27(8):1646-1657. doi: 10.1016/j.bmc.2019.03.009. Epub 2019 Mar 5.

Abstract

Janus kinases (JAKs) play a key role in the proliferation, apoptosis and differentiation of immune cells, and JAKs are considered as an attractive target for the treatment of inflammatory and autoimmune diseases. Here we show the design and optimization of pyrimidine-4,6-diamine derivatives as selectivity JAK3 inhibitors. Compound 11e, which might interact with unique cysteine (Cys909) residue in JAK3, exhibited excellent JAK3 inhibitory activity (IC50 = 2.1 nM) and high JAK kinase selectivity. In cellular assay, 11e showed moderate potency inhibiting IL-2-stimulated T cell proliferation. The data supports the further development of novel JAKs inhibitors.

Keywords: Cys909; JAK3 inhibitors; Janus kinase; Pyrimidine-4,6-diamine derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Proliferation / drug effects
  • Diamines / chemistry*
  • Diamines / metabolism
  • Diamines / pharmacology
  • Drug Design*
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / metabolism
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Rats
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism

Substances

  • Diamines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • pyrimidine-4,6-diamine
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3