fumarates and Arthritis--Rheumatoid

YM-393059 is a novel phosphodiesterase (PDE) 7 and PDE4 dual inhibitor that inhibits PDE7A with high potency (IC50=14 nM) and PDE4 with moderate potency (IC50=630 nM). It inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha production in mice with an ED50 value of 2.1 mg/kg [Yamamoto, S., Sugahara, S., Naito, R., Ichikawa, A., Ikeda, K., Yamada, T., Shimizu, Y., 2006. The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. Eur. J. Pharmacol. 541, 106-114.]. In this study, we investigated the therapeutic potential of YM-393059 for the treatment of rheumatoid arthritis in several animal models. YM-393059 was found to inhibit LPS-induced interleukin (IL)-1beta production in mice with an ED50 value of 16.6 mg/kg, but it had only a slight effect on IL-6 production. YM-393059 and cyclosporine significantly suppressed arthritis development at doses of 30-100 mg/kg and 20 mg/kg, respectively, in the mice collagen-induced arthritis model. YM-393059 (100 mg/kg) significantly inhibited increases in the serum immunoglobulin G level that occurred in response to autoantigenic collagen in arthritic mice, whereas cyclosporine (20 mg/kg) did not. In contrast, cyclosporine completely suppressed the acute rejection of cardiac allografts in rats, whereas YM-393059 did not, even at a dose of 100 mg/kg. YM-393059 potently inhibited proinflammatory cytokine production and selectively suppressed the response to the autoantigen without affecting the response to alloantigens. These results suggest that YM-393059 is an attractive compound for the treatment of autoimmune disorders such as rheumatoid arthritis.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Antibody Formation; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 7; Cyclosporine; Dose-Response Relationship, Drug; Fumarates; Graft Survival; Heart Transplantation; Immunoglobulin G; Immunosuppressive Agents; Indoles; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Phosphodiesterase Inhibitors; Rats; Rats, Inbred Lew; Sulfonamides; Time Factors; Transplantation, Homologous

Topics: Acids; Arthritis; Arthritis, Rheumatoid; Breast Neoplasms; Chromatography; Citric Acid Cycle; Female; Fumarates; Glutarates; Histocytochemistry; Hodgkin Disease; Humans; Neoplasms; Osteosarcoma; Rectal Neoplasms; Sarcoma; Stomach Neoplasms; Stomach Ulcer; Succinates; Thyroid Neoplasms; Uric Acid; Urine; Uterine Cervical Neoplasms; Uterine Neoplasms