Pharmacological profile of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on acute and chronic inflammation models

Eur J Pharmacol. 2006 Nov 21;550(1-3):166-72. doi: 10.1016/j.ejphar.2006.08.023. Epub 2006 Aug 30.

Abstract

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.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Acute Disease
  • Animals
  • Anti-Inflammatory Agents*
  • Carrageenan
  • Chronic Disease
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclic Nucleotide Phosphodiesterases, Type 7
  • Cyclosporine / pharmacology
  • Dermatitis, Contact / drug therapy
  • Edema / chemically induced
  • Edema / drug therapy
  • Erythrocytes / immunology
  • Fumarates / pharmacology*
  • Hypersensitivity, Delayed / drug therapy
  • Immunosuppressive Agents / pharmacology
  • Indoles / pharmacology*
  • Inflammation / drug therapy*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Peritonitis / chemically induced
  • Peritonitis / drug therapy
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Sheep / immunology
  • Sulfonamides / pharmacology*
  • Toluene 2,4-Diisocyanate
  • Zymosan

Substances

  • Anti-Inflammatory Agents
  • Fumarates
  • Immunosuppressive Agents
  • Indoles
  • 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
  • Phosphodiesterase Inhibitors
  • Sulfonamides
  • Toluene 2,4-Diisocyanate
  • Cyclosporine
  • Carrageenan
  • Zymosan
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclic Nucleotide Phosphodiesterases, Type 7
  • Pde7a protein, mouse
  • Pde7a protein, rat