Pharmacological profile of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on acute and chronic inflammation models.
YM-393059 is a novel phosphodiesterase (PDE) 7A and PDE4 dual inhibitor that inhibits both Th1 [interleukin (IL)-2 and interferon-gamma] and Th2 (IL-4) cytokines in vitro [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]. To characterize the pharmacological profile of YM-393059, its effects on several acute and chronic inflammation models were examined. In acute inflammation models, YM-393059 significantly suppressed the delayed-type hypersensitivity reaction to sheep red blood cells in mice with an ED(50) value of 17.1 mg/kg. YM-393059 failed to suppress paw edema in the carrageenin-induced edema model in rats. These pharmacological effects were similar to those of cyclosporine, a typical T-cell immunosuppressant. However, YM-393059, but not cyclosporine, significantly inhibited zymosan-induced neutrophil accumulation in mice with an ED(50) value of 25.7 mg/kg. In mouse toluene-2,4-diisocyanate-induced contact dermatitis, a chronic inflammation model, YM-393059 and cyclosporine significantly suppressed ear edema at doses of 30 and 20 mg/kg, respectively. In this model, YM-393059 also tended to reduce the serum immunoglobulin E antibody level, whereas cyclosporine dramatically potentiated it. These results suggest that YM-393059 inhibits both Th1- and Th2-cell-dependent reactions and also the function of neutrophils.
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*; D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D002908:Chronic Disease; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D016572:Cyclosporine / Q000494:pharmacology; D003877:Dermatitis, Contact / Q000188:drug therapy; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004912:Erythrocytes / Q000276:immunology; D005650:Fumarates / Q000494:pharmacology*; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology*; D014051:Toluene 2,4-Diisocyanate; D015054:Zymosan; D000096926:Benzenesulfonamides
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D016572:Cyclosporine; D005650:Fumarates; D007166:Immunosuppressive Agents; D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D013449:Sulfonamides; D014051:Toluene 2,4-Diisocyanate; D015054:Zymosan; 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