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.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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Adrenergic alpha-2 Receptor Agonists
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Adrenergic alpha-Agonists / pharmacology
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Animals
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Cells, Cultured
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Cytokines / biosynthesis
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Dose-Response Relationship, Drug
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Enterotoxins / pharmacology
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Fumarates / chemistry
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Fumarates / pharmacology*
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Indoles / chemistry
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Indoles / pharmacology*
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Interleukin-2 / biosynthesis
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Kinetics
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Male
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Mice
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Mice, Inbred BALB C
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Phosphodiesterase Inhibitors / pharmacology*
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Phytohemagglutinins / pharmacology
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Prone Position / physiology
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Pyridines / pharmacology
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Pyrimidinones / pharmacology
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Sleep / drug effects
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Sleep / physiology
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Spleen / cytology
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Spleen / drug effects
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Spleen / metabolism
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
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Th1 Cells / drug effects
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Th1 Cells / metabolism
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Th2 Cells / drug effects
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Th2 Cells / metabolism
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Adrenergic alpha-2 Receptor Agonists
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Adrenergic alpha-Agonists
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Cytokines
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Enterotoxins
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Fumarates
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Indoles
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Interleukin-2
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Isoenzymes
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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
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Phosphodiesterase Inhibitors
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Phytohemagglutinins
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Pyridines
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Pyrimidinones
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Sulfonamides
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Tumor Necrosis Factor-alpha
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YM 976
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enterotoxin B, staphylococcal
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4