title: A new phenylpyrazoleanilide, y-320, inhibits interleukin 17 production and ameliorates collagen-induced arthritis in mice and cynomolgus monkeys.
abstract: Interleukin (IL)-15 and IL-17 are thought to play an important role in the pathogenesis of rheumatoid arthritis (RA) because both pro-inflammatory cytokines are found in synovial fluid of RA patients. In this study, we examined the pharmacological profiles of Y-320, a new phenylpyrazoleanilide immunomodulator. Y-320 inhibited IL-17 production by CD4 T cells stimulated with IL-15 with IC50 values of 20 to 60 nM. Oral administration of Y-320 (0.3 to 3 mg/kg) significantly inhibited the development and progression of arthritis and joint destruction with reduction of IL-17 mRNA expression in arthritic joints of type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 in combination with anti-murine tumor necrosis factor-α monoclonal antibody showed a synergistic effect on mouse CIA. Moreover, therapeutic treatment with Y-320 (0.3 and 1 mg/kg orally) ameliorated CIA in cynomolgus monkeys. Our results suggest that Y-320, an orally active inhibitor for IL-17 production, provides a useful therapy for RA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ushio
authors.forename: Seigo
authors.initials: S
authors.lastname: Ishibuchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Oshita
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Seki
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Kunio
authors.initials: K
authors.lastname: Sugahara
authors.forename: Kunitomo
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Process Chemistry Research Laboratories, CMC Division, Mitsubishi Tanabe Pharma Corporation, 3-16-89, Kashima, Yodogawa-ku, Osaka-shi 532-8505, Japan. Chiba.Kenji@mk.mt-pharma.co.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Chiba