The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo.

Abstract

YM-393059, (+/-)-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, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC50=14 nM) and PDE4 with a moderate potency (IC50=630 nM). In a cell-based assay, YM-393059 was found to inhibit anti-CD3 antibody, Staphylococcal enterotoxin B, and phytohaemagglutinin-induced interleukin (IL)-2 production in mouse splenocytes with IC50 values ranging from 0.48 to 1.1 microM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-gamma and IL-4 production in splenocytes with IC50 values of 1.8 and 2.8 microM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-gamma, and IL-4) production was 20- to 31-fold weaker than that of YM976, a selective PDE4 inhibitor. However, orally administered YM-393059 and YM976 inhibited anti-CD3 antibody-induced IL-2 production equipotently in mice. In addition, YM-393059 inhibited lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo more potently than IL-2 (ED50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of alpha2-adrenoceptor agonist-induced sleep in mice, which is a model for the assessment of the typical side effects caused by PDE4 inhibitors, nausea and emesis. YM-393059 is a novel and attractive compound for the treatment of a wide variety of T-cell-mediated diseases.

• Authors: Satoshi Yamamoto, Shingo Sugahara, Ryo Naito, Atsushi Ichikawa, Ken Ikeda, Toshimitsu Yamada, Yasuaki Shimizu
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 541 Issue 1-2 Pg. 106-14 (Jul 10 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16780833 (Publication Type: Journal Article)

Chemical References

• Adrenergic alpha-2 Receptor Agonists
• Adrenergic alpha-Agonists
• Cytokines
• Enterotoxins
• Fumarates
• Indoles
• Interleukin-2
• Isoenzymes
• 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
• Phytohemagglutinins
• Pyridines
• Pyrimidinones
• Sulfonamides
• Tumor Necrosis Factor-alpha
• YM 976
• enterotoxin B, staphylococcal
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors, metabolism)
• Adrenergic alpha-2 Receptor Agonists
• Adrenergic alpha-Agonists (pharmacology)
• Animals
• Cells, Cultured
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Cytokines (biosynthesis)
• Dose-Response Relationship, Drug
• Enterotoxins (pharmacology)
• Fumarates (chemistry, pharmacology)
• Indoles (chemistry, pharmacology)
• Interleukin-2 (biosynthesis)
• Isoenzymes (antagonists & inhibitors, metabolism)
• Kinetics
• Male
• Mice
• Mice, Inbred BALB C
• Phosphodiesterase Inhibitors (pharmacology)
• Phytohemagglutinins (pharmacology)
• Prone Position (physiology)
• Pyridines (pharmacology)
• Pyrimidinones (pharmacology)
• Sleep (drug effects, physiology)
• Spleen (cytology, drug effects, metabolism)
• Sulfonamides (chemistry, pharmacology)
• T-Lymphocytes (cytology, drug effects, metabolism)
• Th1 Cells (drug effects, metabolism)
• Th2 Cells (drug effects, metabolism)
• Tumor Necrosis Factor-alpha (biosynthesis)