The retinoic acid-related orphan receptor (ROR) is a subclass of orphan nuclear receptors. There are three subtypes, including RORα, RORβ, and RORγ. Importantly, RORγt is a master regulator for differentiation of human Th17 cells. Th17 cell line is a subset of CD4+ T cells that are essential in the immune response. The Th17 cells and the inflammatory cytokines (including IL-17A, IL-17F, etc.) play a central role in the pathogenesis of various autoimmune diseases. These diseases include inflammatory bowel disease, psoriasis, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, and asthma. The biologic targeting IL-17A and the IL-17A receptor have demonstrated clinical efficacy in psoriasis, rheumatoid arthritis, and uveitis. Therefore, Th17 cells have emerged as an attractive target for therapeutic intervention in these immune-related diseases.

In this study, Mitsunori Kono, et al designed a series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists. In particular, TAK-828F is a potent and selective orally available RORγt inverse agonist. Firstly, The active compound showed potent RORγt inverse agonistic activity (reporter IC50=6.1 nM) and excellent selectivity against other ROR isoforms (IC50≥30 000 nM, >5000-fold selectivity against human RORα and RORβ). Secondly, TAK-828F exhibited little activity against other nuclear receptors (>800-fold selectivity for RORγt over the other 20 nuclear receptors in both agonist and antagonist mode). Additionally in animal models, oral administration of TAK-828F (0.3, 1, and 3 mg/kg) exhibited robust and dose-dependent inhibition of IL-17A cytokine expression. The ED80 value was 0.5 mg/kg in a mouse IL23-induced gene expression assay. Furthermore, oral administration of TAK-828F significantly reduced the development of clinical symptoms in mouse experimental autoimmune encephalomyelitis model.

Taken together, TAK-828F is a clinical candidate for the treatment of Th17-driven autoimmune diseases and conducted clinical trials.


J Med Chem. 2018 Apr 12;61(7):2973-2988.