[A new orally active anti-rheumatic drug targets IL-15 and IL-17].
Over production of interleukin (IL)-15 and IL-17 was observed in synovial fluids of rheumatoid arthritis (RA) patients. IL-15 activates T cells and induces IL-17 production whereas IL-17 stimulates synoviocytes to release several mediators of inflammation including IL-6, TNF-alpha, IL-8, and CCL2. Thus, it is presumed that IL-15 and IL-17 play important roles in the pathogenesis of RA. Based on these results, we investigated a new anti-rheumatic drug targets IL-15 and IL-17 and found a new pyrazoleanilide derivative, Y-320 that inhibits IL-15-induced IL-17 production by T cells at 10-nM order. Therapeutic treatment with Y-320 (0.3 to 3 mg/kg orally) significantly inhibited the progression of arthritis and joint destruction in type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 inhibited the elevation of IL-17 mRNA expression in the joint of CIA mice. Concomitant treatment with Y-320 and anti-mouse TNF-alpha antibody showed a synergistic effect in 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, a small molecule inhibitor for IL-17 production, is a candidate for the new class of orally active anti-rheumatic drug.
Chiba
Kenji
K
Research Laboratory III (Immunology), Pharmaceuticals Research Division, Mitsubishi Pharma Corporation.
D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D016503:Drug Delivery Systems; D019409:Interleukin-15 / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D008253:Macaca mulatta; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D018501:Antirheumatic Agents; D019409:Interleukin-15; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha