Pharmacological Properties of JTE-151; A Novel Orally Available RORγ Antagonist That Suppresses Th17 Cell-Related Responses in Vitro and in Vivo.

Retinoid-related orphan receptor-γ (RORγ) is a nuclear receptor that plays important roles in the development and activation of T helper type-17 (Th17) cells. In this study, we characterized the pharmacological profile of JTE-151 ((4S)-6-[(2-chloro-4-methylphenyl)amino]-4-{4-cyclopropyl-5-[cis-3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3yl}-6-oxohexanoic acid), which is a novel RORγ antagonist identified by our group. JTE-151 dissociated co-activator peptide from the human RORγ-ligand binding domain (LBD) and recruited co-repressor peptide into human RORγ-LBD, and potently inhibited the transcriptional activity of RORγ of human, mouse and rat. JTE-151 also demonstrated high selectivity against other receptors in nuclear receptor family. JTE-151 suppressed the differentiation of mouse naïve CD4+ T cells into Th17 cells without affecting the differentiation of those cells into other CD4+ T cell subsets in vitro. In addition, JTE-151 inhibited the production of interleukin-17 (IL-17) but not interferon-γ (IFN-γ) and IL-4 from activated human helper T cells in vitro. Furthermore, treatment with JTE-151 suppressed the production of IL-17 in antigen-sensitized mice and ameliorated the severity of arthritis in mice with collagen-induced arthritis regardless of treatment start date. Based on these results, we reasoned that JTE-151 could serve as a novel therapeutic compound for various autoimmune diseases linked to Th17 cells, such as psoriasis and rheumatoid arthritis.