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A New Phenylpyrazoleanilide, Y-320, Inhibits Interleukin 17 Production and Ameliorates Collagen-Induced Arthritis in Mice and Cynomolgus Monkeys

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Process Chemistry Research Laboratories, CMC Division, Mitsubishi Tanabe Pharma Corporation, 3-16-89, Kashima, Yodogawa-ku, Osaka-shi 532-8505, Japan
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Medicinal Chemistry Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan
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Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan
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Advanced Medical Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2014, 7(1), 1-17; https://doi.org/10.3390/ph7010001
Received: 5 November 2013 / Revised: 16 December 2013 / Accepted: 18 December 2013 / Published: 23 December 2013
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. View Full-Text
Keywords: interleukin 15 (IL-15); interleukin 17 (IL-17); phenylpyrazoleanilide; Y-320; immunomodulator; collagen-induced arthritis (CIA); rheumatoid arthritis (RA) interleukin 15 (IL-15); interleukin 17 (IL-17); phenylpyrazoleanilide; Y-320; immunomodulator; collagen-induced arthritis (CIA); rheumatoid arthritis (RA)
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Ushio, H.; Ishibuchi, S.; Oshita, K.; Seki, N.; Kataoka, H.; Sugahara, K.; Adachi, K.; Chiba, K. A New Phenylpyrazoleanilide, Y-320, Inhibits Interleukin 17 Production and Ameliorates Collagen-Induced Arthritis in Mice and Cynomolgus Monkeys. Pharmaceuticals 2014, 7, 1-17.

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