Skip to main content
SpringerLink
Log in

The inhibition of 5-lipoxygenase by RG 6866

  • Allery, Histamine and Kinins
  • Published:
Agents and Actions Aims and scope Submit manuscript

Abstract

The generation of leukotrienes C4, D4 and E4 from arachidonic acid is dependent upon the activity of 5-lipoxygenase (5-LOX). The effects of RG 6866 (N-methyl-4-benzyloxyphenylacetohydroxamic acid) on the activity of guinea pig 5-LOXin vitro andin vivo were determined in the present study. The generation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) from arachidonic acid by isolated guinea pig peritoneal polymorphonuclear (PMN) cells was inhibited by incubation with RG 6866 (IC50=0.20 μM). A similar effect (IC50=0.23 μM) was observed when 5-HETE production was measured in a supernatant fraction from PMNs. Additionally, the compound did not inhibit3H-LTD4 binding to guinea pig membranes. In actively sensitized guinea pigs pretreated with indomethacin, propranolol and pyrilamine, RG 6866 inhibited antigen-induced systemic anaphylaxis and LTD4-dependent bronchoconstriction in a dose-dependent manner following oral administration. In the pulmonary anaphylaxis model, significant (p<0.05) inhibition of the mortality was observed within 30 min and maintained through four hours after treatment with RG 6866 (50 mg/kg i.g.). Finally, orally administered RG 6866 inhibited the formation of LTC4 in these animals with an ED50=24.0 mg/kg. These findings indicate that RG 6866 is an inhibitor of 5-LOX bothin vitro andin vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. P. M. Simmons, J. A. Salmon and S. Moncada,The release of leukotriene B 4 during experimental inflammation. Biochem. Pharma.32, 1353–1359 (1983).

    Google Scholar 

  2. M. J. H. Smith, A. W. Ford-Hutchinson and M. A. Bray,Leukotriene B: A potential mediator of inflammation. J. Pharm. Pharmac.32, 517–518 (1980).

    Google Scholar 

  3. J. H. Fleisch, L. E. Rinkema, K. D. Haisch, D. Swanson-Bean, T. Goodson, P. P. K. Ho and W. S. Marshall,LY-171883, 1-[2-hydroxy-3-propyl-4-4-(1H)-tetrazol-5-yl) butoxy] phenyl-ethanone, an orally active leukotriene D 4 antagonist. J. Pharmac. Exp. Ther.233, 148–157 (1985).

    Google Scholar 

  4. G. W. Carnathan, J. H. Sanner, J. M. Thompson, C. M. Prusa and M. Miyano,Antagonism of the in vivo and in vitro effects of leukotriene D 4 by SC-39070 in guinea pigs. Agents and Actions20, 124–132 (1987).

    PubMed  Google Scholar 

  5. D. W. P. Hay, R. M. Muccitelli, S. S. Tucker, L. M. Vickery-Clark, K. A. Wilson, J. G. Gleason, R. F. Hall, M. A. Wasserman and T. J. Torphy,Pharmacologic profile of SK&F 104353: A novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways. J. Pharmacol. Exp. Ther.243, 474–481 (1987).

    PubMed  Google Scholar 

  6. D. W. Snyder, R. E. Giles, R. A. Keith, Y. K. Yee and R. D. Krell,in vitro pharmacology of ICI-198615: A novel, potent and selective peptide leukotriene antagonist. J. Pharmac. Exp. Ther.243, 548–556 (1987).

    Google Scholar 

  7. D. E. Griswold, P. J. Marshall, E. F. Webb, R. Godfrey, J. Newton Jr., M. J. DiMartino, H. M. Sarau, J. G. Gleason, G. Poste and N. Hanna,SK&F 86002: A structurally novel anti-inflammatory agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid. Biochem. Pharmac.36, 3463–3470 (1987).

    Google Scholar 

  8. C. S. McFarlane, R. Hamel and A. W. Ford-Hutchinson,Effects of a 5-lipoxygenase inhibitor (L-651,392)on primary and late pulmonary responses to ascaris antigen in the squirrel monkey. Agents and Actions22, 63–68 (1987).

    PubMed  Google Scholar 

  9. S. M. Coutts, A. Khandwala, R. Van Inwegen, U. Chakraborty, J. Musser, J. Bruens, N. Jariwala, V. Dally-Meade, R. Ingram, T. Pruss, H. Jones, E. Neiss and I. Weinryb,Arylmethyl phenyl ethers: A new class of specific inhibitor of 5-lipoxygenase. InProstaglandins, Leukotrienes and Lipoxins. (Ed. J. M. Bailey) pp. 627–637, Plenum Publishing Corp., New York 1985.

    Google Scholar 

  10. R. G. Van Inwegen, A. Khandwala, R. Gordon, P. Sonnino, S. Coutts and S. Jolly,REV-5901: An orally effective peptidoleukotriene antagonist, detailed biochemical/pharmacological profile. J. Pharma. Exp. Ther.241, 117–124 (1987).

    Google Scholar 

  11. D. Sweeney, J. Travis, R. Gordon, S. Coutts, N. Jariwala, F. Huang and G. Carnathan,The effect of a novel inhibitor of 5-lipoxygenase on pulmonary anaphylaxis in sensitized guinea pigs. Fed. Proc.46, 1302 (1987).

    Google Scholar 

  12. R. G. Van Inwegen, G. W. Nuss and G. W. Carnathan,Antagonism of peptidoleukotrienes and inhibition of systemic anaphylaxis by RG-12525 in guinea pigs. Life Sciences44, 799–807 (1989).

    PubMed  Google Scholar 

  13. B. M. Weichman, R. M. Muccitelli, R. R. Osborn, D. A. Holden, J. G. Gleason and M. A. Wasserman,In vitro and in vivo mechanisms of leukotriene-mediated bronchoconstriction in the guinea pig. J. Pharma. Exp. Ther.222, 202–208 (1982).

    Google Scholar 

  14. C. J. Hanna, M. K. Bach, P. D. Pare and R. R. Schellenberg,Slow-reacting substances (leukotrienes) contract human airway and pulmonary vascular smooth muscle in vitro. Nature (London)290, 343–344 (1981).

    Google Scholar 

  15. J. Chang, M. D. Skowronek, M. L. Cherney and A. J. Lewis,Differential effects of putative lipoxygenase inhibitors on arachidonic acid metabolism in cell-free and intact cell preparations. Inflammation8, 143–155 (1984).

    PubMed  Google Scholar 

  16. T. Yoshimoto, C. Yokoyama, K. Ochi, S. Yamamoto, Y. Maki, Y. Ashida, S. Terao and M. Shiraishi,2,3,5-Trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-1,4-benzoquinone (AA-861), A selective inhibitor of the 5-lipoxygenase reaction and the biosynthesis of slow-reacting substance of anaphylaxis. Biochemica Et Biophysica Acta713, 470–473 (1982).

    Google Scholar 

  17. P. Andersson and H. Bergstrand,Antigen-induced bronchial anaphylaxis in actively sensitized guinea-pig: Effects of longterm treatment with sodium cromoglycate and aminophylline. Br. J. Pharmac.74, 601–609 (1981).

    Google Scholar 

  18. J. M. Hand, S. F. Schwalm and A. J. Lewis,Antagonism of antigen-induced contraction of isolated guinea-pig trachea by 5-lipoxygenase inhibitors. Int. Archs. Allergy Appl. Immun.79, 8–13 (1986).

    Google Scholar 

  19. R. O. Salonen,Actions of bronchodilator drugs, glucocorticoid and their combinations on airways in rats and guinea pigs. Acta Pharma. Toxicol.57, Suppl. III, 1–38 (1985).

    Google Scholar 

  20. N. C. Turner and C. T. Dollery,Release of arachidonic acid metabolites and histamine from sensitized guinea-pig lung following antigen challenge. Br. J. Pharmac.93, 751–758 (1988).

    Google Scholar 

Download references

Author information

Author notes

  1. R. J. Gordon

    Present address: Sterling Winthrop Research Institute, 12144, Rensselaer, NY, USA

Authors and Affiliations

  1. Department of Immunobiology and Medicinal Chemistry, Rorer Central Research, 640 Allendale Road, 19406, King of Prussia, PA, USA

    G. W. Carnathan, D. M. Sweeney, J. J. Travis, R. J. Gordon, C. A. Sutherland, N. Jariwala, M. Clearfield, S. O'Rourke, F. C. Huang & R. G. Van Inwegen

Authors
  1. G. W. Carnathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. M. Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. J. Travis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. J. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. A. Sutherland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Jariwala
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Clearfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. O'Rourke
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. C. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. G. Van Inwegen
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Previously designated as REV-6866 in a preliminary communication.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carnathan, G.W., Sweeney, D.M., Travis, J.J. et al. The inhibition of 5-lipoxygenase by RG 6866. Agents and Actions 28, 204–211 (1989). https://doi.org/10.1007/BF01967402

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01967402

Keywords

Search

Navigation