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

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.

• Authors: Satoshi Yamamoto, Shingo Sugahara, Ken Ikeda, Yasuaki Shimizu
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 550 Issue 1-3 Pg. 166-72 (Nov 21 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17010967 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• 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, 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, drug therapy)
• Phosphodiesterase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sheep (immunology)
• Sulfonamides (pharmacology)
• Toluene 2,4-Diisocyanate
• Zymosan