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Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide

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Abstract

Objective and design

To examine the effects of a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2-inhibitor, JTP-74057, on inflammatory arthritis development, and compare its anti-arthritic effect with leflunomide.

Materials

Human, mouse, and rat peripheral blood mononuclear cells (PBMCs) were used. Lewis rats and DBA/1J mice were used for animal models.

Treatment

JTP-74057 was tested between 0.1–100 nM in in-vitro studies. JTP-74057 (0.01–0.3 mg/kg) and leflunomide (2–10 mg/kg) were administered orally in vivo.

Methods

PBMCs were stimulated with lipopolysaccharide. Adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) was induced in Lewis rats or DBA1/J mice, respectively.

Results

JTP-74057 blocked tumor necrosis factor-α and interleukin-6 production from PBMCs. AIA and CIA development were suppressed almost completely by 0.1 mg/kg of JTP-74057 or 10 mg/kg of leflunomide. In the CIA, JTP-74057, but not leflunomide, suppressed collagen-reactive T-cell proliferation ex vivo, whereas leflunomide, but not JTP-74057, suppressed anti-collagen antibody production.

Conclusions

JTP-74057 exerts potent anti-arthritic effects with a different profile from leflunomide, suggesting that JTP-74057 may be useful as a new therapeutic reagent in the treatment of rheumatoid arthritis.

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Acknowledgments

We would like to thank Hisashi Kawasaki and Hiroyuki Abe for synthesis of the compound, and Junji Maruhashi and Minako Tanimoto for their excellent technical assistance.

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Authors and Affiliations

  1. Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan

    Takayuki Yamaguchi, Reina Kakefuda, Atsuo Tanimoto, Yoshihiro Watanabe & Nobuyuki Tajima

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  1. Takayuki Yamaguchi
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  2. Reina Kakefuda
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  3. Atsuo Tanimoto
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  4. Yoshihiro Watanabe
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  5. Nobuyuki Tajima
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Correspondence to Takayuki Yamaguchi.

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Responsible editor: John Di Battista.

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Yamaguchi, T., Kakefuda, R., Tanimoto, A. et al. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide. Inflamm. Res. 61, 445–454 (2012). https://doi.org/10.1007/s00011-011-0431-5

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  • DOI: https://doi.org/10.1007/s00011-011-0431-5

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