A novel 2,4-diaminopyrimidine derivative as selective inhibitor of protein kinase C theta prevents allograft rejection in a rat heart transplant model

Bioorg Med Chem. 2018 Nov 1;26(20):5499-5509. doi: 10.1016/j.bmc.2018.09.029. Epub 2018 Sep 24.

Abstract

Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and is an attractive target for the treatment of T cell-mediated diseases such as transplant rejection and autoimmune disease. To identify PKCθ inhibitors, we focused on the 2,6-diamino-3-carbamoyl-5-cyanopyrazine derivative 2, which exhibited moderate PKCθ inhibitory activity. Optimization of 2 identified the 2,4-diamino-5-cyanopyrimidine derivative 16c, which exhibited potent PKCθ inhibitory activity and showed good selectivity against other PKC isozymes. Compound 16c prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.

Keywords: Immunosuppressant; Protein kinase C theta (PKCθ); Selective.

MeSH terms

  • Animals
  • Female
  • Graft Rejection / metabolism
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects
  • Heart Transplantation / adverse effects
  • Heart Transplantation / methods*
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase C-theta / antagonists & inhibitors*
  • Protein Kinase C-theta / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Rats, Sprague-Dawley
  • Transplantation, Homologous / adverse effects
  • Transplantation, Homologous / methods

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • 2,4-diaminopyrimidine
  • Protein Kinase C-theta