Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3

Bioorg Med Chem. 2016 Oct 1;24(19):4711-4722. doi: 10.1016/j.bmc.2016.08.007. Epub 2016 Aug 6.

Abstract

In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.

Keywords: Immunomodulator; JAK3 (Janus kinase 3); Transplant rejection; hERG (human ether-a-go-go related gene).

MeSH terms

  • 6-Aminonicotinamide / analogs & derivatives*
  • 6-Aminonicotinamide / chemical synthesis
  • 6-Aminonicotinamide / pharmacology*
  • 6-Aminonicotinamide / therapeutic use
  • Animals
  • Graft Rejection / prevention & control
  • Heart Transplantation
  • Humans
  • Immunologic Factors / chemical synthesis
  • Immunologic Factors / chemistry*
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / metabolism
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Rats

Substances

  • Immunologic Factors
  • Protein Kinase Inhibitors
  • 6-Aminonicotinamide
  • Janus Kinase 3