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Inflamm Res. 2012 May;61(5):445-54. doi: 10.1007/s00011-011-0431-5. Epub 2012 Jan 14.

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

Author information

1
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Murasaki-cho, Takatsuki, Osaka, Japan. takayuki.yamaguchi@jt.com

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.

PMID:
22245957
DOI:
10.1007/s00011-011-0431-5
[Indexed for MEDLINE]

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