Pharmacological evaluation of TAK-828F, a novel orally available RORγt inverse agonist, on murine chronic experimental autoimmune encephalomyelitis model

J Neuroimmunol. 2019 Oct 15:335:577016. doi: 10.1016/j.jneuroim.2019.577016. Epub 2019 Jul 25.

Abstract

We investigated the potency of TAK-828F, a RORγt inverse agonist, in murine experimental autoimmune encephalomyelitis (EAE) model. TAK-828F inhibited the differentiation of Th17 and Th1/17 cells in inguinal lymph node. Increase of these cells in central nervous system (CNS) was also inhibited by TAK-828F. Prophylactic and therapeutic treatments of TAK-828F were efficacious in the model. Plasma concentration of TAK-828F was higher than that in CNS. These results indicate that TAK-828F mainly acts at peripheral and results in the reduction of Th17- and Th1/17-dependent inflammation in CNS. Blocking RORγt may be a promising strategy for treatment of multiple sclerosis.

Keywords: Experimental autoimmune encephalomyelitis; TAK-828F; Th1/17; Th17.

MeSH terms

  • Acetates / pharmacology*
  • Animals
  • Cell Differentiation / drug effects
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Naphthyridines / pharmacology*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th17 Cells / drug effects
  • Th17 Cells / immunology

Substances

  • Acetates
  • Naphthyridines
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • TAK-828F