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Research ArticleArticle

SB 207499 (Ariflo), a Second Generation Phosphodiesterase 4 Inhibitor, Reduces Tumor Necrosis Factor α and Interleukin-4 Production in vivo

Don E. Griswold, Edward F. Webb, Alison M. Badger, Peter D. Gorycki, Patricia A. Levandoski, Mary A. Barnette, Marilyn Grous, Siegfried Christensen and Theodore J. Torphy
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 705-711;
Don E. Griswold
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Edward F. Webb
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Alison M. Badger
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Peter D. Gorycki
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Patricia A. Levandoski
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Mary A. Barnette
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Marilyn Grous
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Siegfried Christensen
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Theodore J. Torphy
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Abstract

The ability of the second generation phosphodiesterase 4 inhibitor SB 207499 (Ariflo), [c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane carboxylic acid], to inhibit inflammatory cytokine production in vivo was evaluated and compared to that of rolipram, a first generation phosphodiesterase 4 inhibitor. To examine human tumor necrosis factor alpha (TNFα) production, human monocytes were adoptively transferred into Balb/c mice and challenged with lipopolysaccharide (LPS). In this model, SB 207499 inhibited human TNFα production with oral ED50 of 4.9 mg/kg. Similarly, R-rolipram inhibited human TNFα production with an ED50of 5.1 mg/kg, p.o. In contrast to their equipotent activity against TNFα production, SB 207499 (ED50 = 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in reversing reserpine-induced hypothermia, a model of antidepressant activity. In time course studies, SB 207499 (30 mg/kg, p.o.) inhibited TNFα production for at least 10 hr; substantial plasma concentrations of SB 207499 were detected over the same interval. The ability of SB 207499 to modulate interleukin-4 productionin vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. In this model, topical administration of SB 207499 (1000 μg) inhibited intralesional concentrations of interleukin-4 (55%; P < .01). The results demonstrate that SB 207499 is a potent inhibitor of inflammatory cytokine production in a variety of settings in vivo. Moreover, although it is as potent as R-rolipram in inhibiting TNFα production, it has substantially less central nervous system activity. Thus SB 207499 represents an excellent candidate with which to evaluate the antiinflammatory potential of PDE4 inhibitors.

Footnotes

  • Send reprint requests to: Dr. Don E. Griswold, Associate Director, Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939.

  • Abbreviations:
    Cyclic AMP
    3′-5′cyclic adenosine monophosphate
    CNS
    central nervous system
    DPBS
    Dulbecco’s phosphate-bufferred saline without calcium and magnesium
    ELISA
    enzyme-linked immunosorbant assay
    HPDE4
    PDE4 conformer that binds rolipram with high affinity (previously termed “high affinity rolipram binding site”)
    LPS
    lipopolysaccharide
    LPDE4
    PDE4 conformer that binds rolipram with low affinity
    PDE4
    phosphodiesterase type 4
    TNFα
    tumor necrosis factor α
    IL-4
    interleukin-4
    • Received February 18, 1998.
    • Accepted June 26, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

SB 207499 (Ariflo), a Second Generation Phosphodiesterase 4 Inhibitor, Reduces Tumor Necrosis Factor α and Interleukin-4 Production in vivo

Don E. Griswold, Edward F. Webb, Alison M. Badger, Peter D. Gorycki, Patricia A. Levandoski, Mary A. Barnette, Marilyn Grous, Siegfried Christensen and Theodore J. Torphy
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 705-711;

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Research ArticleArticle

SB 207499 (Ariflo), a Second Generation Phosphodiesterase 4 Inhibitor, Reduces Tumor Necrosis Factor α and Interleukin-4 Production in vivo

Don E. Griswold, Edward F. Webb, Alison M. Badger, Peter D. Gorycki, Patricia A. Levandoski, Mary A. Barnette, Marilyn Grous, Siegfried Christensen and Theodore J. Torphy
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 705-711;
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