title: Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Human, mouse, and rat peripheral blood mononuclear cells (PBMCs) were used. Lewis rats and DBA/1J mice were used for animal models.
  
  
  METHODS
  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.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Murasaki-cho, Takatsuki, Osaka, Japan. takayuki.yamaguchi@jt.com
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Reina
authors.initials: R
authors.lastname: Kakefuda
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tajima
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D000077339:Leflunomide; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008813:Mice, Inbred ICR; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D024043:Collagen Type II; D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D007555:Isoxazoles; D008070:Lipopolysaccharides; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D000077339:Leflunomide