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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Pharmacological Profile of a Novel Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a 1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities

Alexandre Trifilieff, Daniel Wyss, Christoph Walker, Lazzaro Mazzoni and Rene Hersperger
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 241-248; DOI: https://doi.org/10.1124/jpet.301.1.241
Alexandre Trifilieff
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Daniel Wyss
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Christoph Walker
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Lazzaro Mazzoni
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Rene Hersperger
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Abstract

We investigated the pharmacology of a new class of phosphodiesterase 4 (PDE4) inhibitor, 6,8-disubstituted 1,7-naphthyridines, by using 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171) as a representative compound and compared its potency with the most advanced PDE4 inhibitor, undergoing clinical trials, Ariflo [cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexanecarboxylic acid)]. NVP-ABE171 inhibited the activity of phosphodiesterase 4A, 4B, 4C, and 4D with respective IC50 values of 602, 34, 1230, and 1.5 nM. Ariflo was about 40 times less potent. In human cells, NVP-ABE171 inhibited the eosinophil and neutrophil oxidative burst, the release of cytokines by T cells, and the tumor necrosis factor-α release from monocytes, in the nanomolar range. Ariflo presented a similar inhibition profile but was 7 to 50 times less potent. In BALB/c mice challenged with lipopolysaccharide, NVP-ABE171 inhibited the airway neutrophil influx and activation with an ED50 in the range of 3 mg/kg. Ariflo was inactive up to a dose of 10 mg/kg. In ovalbumin sensitized Brown Norway rats, NVP-ABE171 inhibited the lipopolysaccharide-induced airway neutrophil influx and activation (ED50 of 0.2 mg/kg) and the ovalbumin-induced airway eosinophil influx and activation (ED50 of 0.1 mg/kg). Ariflo was about 100 times less potent in both models. In the ovalbumin model, NVP-ABE171 had a duration of action of more than 24 h. NVP-ABE171 is a novel PDE4 inhibitor that shows activity both in vitro on human inflammatory cells and in vivo in animal models of lung inflammation. This compound class may have potential for the treatment of airway inflammatory conditions such as asthma and chronic obstructive pulmonary diseases.

Footnotes

  • Abbreviations:
    PDE
    phosphodiesterase
    NVP-ABE171
    4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid
    DMSO
    dimethyl sulfoxide
    FCS
    fetal calf serum
    PBS
    phosphate-buffered saline
    IL
    interleukin
    IFN
    interferon
    ELISA
    enzyme-linked immunosorbent assay
    TNF
    tumor necrosis factor
    LPS
    lipopolysaccharide
    Ariflo
    cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexanecarboxylic acid)
    V 11294A
    3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine hydrochloride
    YM976
    4-3(chlorophenyl-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one
    LAS 31025
    3-(p-chlorophenyl)-1-propylxanthine
    TES
    2-{[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino}ethanesulfonic acid
    • Received October 8, 2001.
    • Accepted December 5, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Pharmacological Profile of a Novel Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a 1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Pharmacological Profile of a Novel Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a 1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities

Alexandre Trifilieff, Daniel Wyss, Christoph Walker, Lazzaro Mazzoni and Rene Hersperger
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 241-248; DOI: https://doi.org/10.1124/jpet.301.1.241

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Pharmacological Profile of a Novel Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a 1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities

Alexandre Trifilieff, Daniel Wyss, Christoph Walker, Lazzaro Mazzoni and Rene Hersperger
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 241-248; DOI: https://doi.org/10.1124/jpet.301.1.241
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