ABT-761 Attenuates Bronchoconstriction and Pulmonary Inflammation in Rodents

  1. Randy L. Bell,
  2. Richard R. Harris,
  3. Peter E. Malo,
  4. Jennifer B. Bouska,
  5. Thomas K. Shaughnessy,
  6. Keren I. Hulkower,
  7. Clint D. W. Brooks and
  8. George W. Carter
  1. Immunosciences Research Area, Abbott Laboratories, Abbott Park, Illinois

    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    • 1 P. Malo and R. Bell, unpublished observations.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.
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    1. JPET March 1, 1997 vol. 280 no. 3 1366-1373
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