Amelioration of collagen-induced arthritis in mice by a novel phosphodiesterase 7 and 4 dual inhibitor, YM-393059.
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.
Yamamoto
Satoshi
S
Pharmacology Research Laboratories, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. satoshi-yamamoto@jp.astellas.com
Sugahara
Shingo
S
Ikeda
Ken
K
Shimizu
Yasuaki
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007074:Immunoglobulin G / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014184:Transplantation, Homologous; D000096926:Benzenesulfonamides
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D018501:Antirheumatic Agents; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D016572:Cyclosporine; D005650:Fumarates; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007211:Indoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D010726:Phosphodiesterase Inhibitors; D013449:Sulfonamides; C514969:N-(4,6-dimethylpyrimidin-2-yl)-4-(2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzenesulfonamide difumarate; D000096926:Benzenesulfonamides; C517459:Pde7a protein, mouse; C517461:Pde7a protein, rat