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

• Published in: European journal of pharmacology 2006-07, Vol.541 (1), p.106-114
• Main Authors: Yamamoto, Satoshi, Sugahara, Shingo, Naito, Ryo, Ichikawa, Atsushi, Ikeda, Ken, Yamada, Toshimitsu, Shimizu, Yasuaki
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists - pharmacology; Animals; Biological and medical sciences; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 4; Cytokines - biosynthesis; Dose-Response Relationship, Drug; Enterotoxins - pharmacology; Fumarates - chemistry; Fumarates - pharmacology; Indoles - chemistry; Indoles - pharmacology; Interleukin-2; Interleukin-2 - biosynthesis; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Kinetics; Male; Medical sciences; Mice; Mice, Inbred BALB C; Pharmacology. Drug treatments; Phosphodiesterase 4; Phosphodiesterase 7A; Phosphodiesterase Inhibitors - pharmacology; Phytohemagglutinins - pharmacology; Prone Position - physiology; Pyridines - pharmacology; Pyrimidinones - pharmacology; Sleep - drug effects; Sleep - physiology; Spleen - cytology; Spleen - drug effects; Spleen - metabolism; Sulfonamides - chemistry; Sulfonamides - pharmacology; T-cell; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Th1 Cells - drug effects; Th1 Cells - metabolism; Th2 Cells - drug effects; Th2 Cells - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor necrosis factor-α; YM-393059; YM976
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2006.05.007

YM-393059, (±)- N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1 H-indol-1-yl]benzenesulfonamide difumarate, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC 50 = 14 nM) and PDE4 with a moderate potency (IC 50 = 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 IC 50 values ranging from 0.48 to 1.1 μM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-γ and IL-4 production in splenocytes with IC 50 values of 1.8 and 2.8 μM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-γ, 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-α production in vivo more potently than IL-2 (ED 50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of α 2-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.