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OtherPULMONARY PHARMACOLOGY

ABT-761 Attenuates Bronchoconstriction and Pulmonary Inflammation in Rodents

Randy L. Bell, Richard R. Harris, Peter E. Malo, Jennifer B. Bouska, Thomas K. Shaughnessy, Keren I. Hulkower, Clint D. W. Brooks and George W. Carter
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1366-1373;
Randy L. Bell
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Richard R. Harris
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Peter E. Malo
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Jennifer B. Bouska
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Thomas K. Shaughnessy
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Keren I. Hulkower
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Clint D. W. Brooks
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George W. Carter
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Abstract

Our primary goal has been to discover leukotriene biosynthesis inhibitors with characteristics that are appropriate for use as clinical agents. The success of the use of zileuton in the treatment of asthma led us to explore further the use of theN-hydroxyurea class of 5-lipoxygenase inhibitors as longer-acting compounds with good lung penetration. A variety ofin vitro and in vivo methods were used to evaluate a large number of compounds, from which ABT-761 [(R)-N-(3-(5-(4-fluorophenylmethyl)thien-2-yl)-1-methyl-2-propynyl)-N-hydroxyurea] was selected for study. ABT-761 exhibited potent and selective inhibition of leukotriene formation both in vitro andin vivo. More importantly, the compound potently inhibited antigen-induced bronchospasm in guinea pigs when given either prophylactically or therapeutically. In addition, ABT-761 was a potent inhibitor of eosinophil influx into the lungs of Brown Norway rats. These data provide added support for the role of leukotrienes in both bronchospasm and eosinophilic inflammation and characterize ABT-761 as a particularly potent inhibitor of leukotrienes formed in pulmonary tissues. These data combined with the excellent pharmacokinetic characteristics of the compound indicate its potential use in the treatment of leukotriene-dependent human disease.

Footnotes

  • Send reprint requests to: Dr. Randy L. Bell, Abbott Laboratories, Department 47K, Building AP9, 100 Abbott Park Road, Abbott Park, IL 60064.

  • 1 P. Malo and R. Bell, unpublished observations.

  • Abbreviations:
    LTB4
    leukotriene B4
    LTD4
    leukotriene D4
    5-HETE
    5-hydroxyeicosatetraenoic acid
    12-HETE
    12-hydroxyeicosatetraenoic acid
    5-HPETE
    5-hydroperoxyeicosatetraenoic acid
    RBL-1
    rat basophilic leukemia cells
    DMSO
    dimethylsulfoxide
    PBS
    phosphate buffered saline
    EIA
    enzyme immunoassay
    HPMC
    hydroxypropyl methyl cellulose
    AA
    arachidonic acid
    TXB2
    thromboxane B2
    Cdyn
    dynamic compliance
    PMNL
    polymorphonuclear leukocytes
    FLAP
    5-lipoxygenase activating protein
    • Received July 15, 1996.
    • Accepted November 22, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherPULMONARY PHARMACOLOGY

ABT-761 Attenuates Bronchoconstriction and Pulmonary Inflammation in Rodents

Randy L. Bell, Richard R. Harris, Peter E. Malo, Jennifer B. Bouska, Thomas K. Shaughnessy, Keren I. Hulkower, Clint D. W. Brooks and George W. Carter
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1366-1373;

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OtherPULMONARY PHARMACOLOGY

ABT-761 Attenuates Bronchoconstriction and Pulmonary Inflammation in Rodents

Randy L. Bell, Richard R. Harris, Peter E. Malo, Jennifer B. Bouska, Thomas K. Shaughnessy, Keren I. Hulkower, Clint D. W. Brooks and George W. Carter
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1366-1373;
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  • Effects of 8-Bromo-Cyclic GMP on Membrane Potential of Single Swine Tracheal Smooth Muscle Cells
  • Inhibition of 5-Lipoxygenase Diminishes Neurally Evoked Tachykinergic Contraction of Guinea Pig Isolated Airway
  • Dehydroepiandrosterone and Analogs Inhibit DNA Binding of AP-1 and Airway Smooth Muscle Proliferation
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