Skip to main content
SpringerLink
Log in

Effects of Tebufelone (NE-11740), a new anti-inflammatory drug, on arachidonic acid metabolism

  • Inflammation
  • Published:
Agents and Actions Aims and scope Submit manuscript

Abstract

Tebufelone is a novel nonsteroidal anti-inflammatory drug (NSAID), of the di-tert-butylphenol (DTBP) class, which displays potent anti-inflammatory, analgesic and anti-pyretic properties in a variety of animal models. In this report, the effects of Tebufelone on arachidonic acid (AA) metabolism are reviewed. Tebufelone potently inhibits the formation of prostaglandins (PGE2) a key mediator of pain and inflammation, in isolated enzyme preparations (IC50=1.5 μM,K I=0.35 μM), twoin vitro cellular systems: rat peritoneal macrophages (IC50=0.02 μM) and human whole blood (IC50=0.08 μM), andex vivo in man. In addition to PGE2 inhibition, which is common to all NSAIDs, higher concentrations of Tebufelone block thein vitro formation of products of the lipoxygenase pathway [leukotrienes (LTB4)] in rat macrophages (IC50=20 μM) and human whole blood (IC50=22 μM). Substrate incorporation studies (14C-AA) indicate that Tebufelone reversibly inhibits cyclooxygenase (CO) and 5-lipoxygenase (5-LO) enzymes rather than regulating the release of AA. Tebufelone was shown to be a more potent CO inhibitor than indomethacin and a less potent 5-LO inhibitor than RG-5901. Comparisons to structurally related compounds under development (E-5110, Esai; KME-4, Kanagafuchi), found Tebufelone to be the most potent CO inhibitorin vitro. All three DTBP compounds were equipotent 5-LO inhibitors. It is likely that Tebufelone's inhibitory effects on AA metabolism are, in part, responsible for itsin vivo efficacy and enhanced safety profile.

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. S. Hammarstrom,Leukotrienes. Ann. Rev. Biochem.52, 355–377 (1983).

    Article  PubMed  Google Scholar 

  2. C. Granstrom, U. Diczfalusy, M. Hamberg, G. Hansson, C. Malmsten and B. Samuelsson, Thromboxane A2: biosynthesis and effects on platelets. In:Prostaglandins and the Cardiovascular System. (Ed. J. A. Oates) pp. 15–58, Raven New York, 1982.

    Google Scholar 

  3. C. Pace-Asciak and R. Gryglewski,The prostacyclins. In:Prostaglandins and Related Substances (Eds. C. Pace-Asciak and E. Granstrom) pp 1–44, Elsever, Amsterdam 1983.

    Google Scholar 

  4. B. Samuelsson, M. Goldyne, E. Granstrom, M. Hamberg, S. Hammarstrom and C. Malmsten,Prostaglandins and thromboxanes. Ann. Rev. Biochem.47, 997–1029 (1978).

    Google Scholar 

  5. E. Oliw, E. Granstrom and E. Anggard,Prostaglandins and Related Substances (Ed. C. Pace-Asciak and E. Granstrom) pp. 95–126, Elsevier, Amsterdam 1983.

    Google Scholar 

  6. J. C. McCllff,Prostaglandins, prostacyclin and thromboxanes. Ann. Rev. Pharmacol. Toxicol.21, 479–509 (1981).

    Article  Google Scholar 

  7. P. Davies, P. J. Bailey, M. M. Goldenberg and A. W. Ford Hutchinson,The role of arachidonic acid oxygenation products in pain and inflammation. Ann. Rev. Immunol.2, 333–357 (1984).

    Article  Google Scholar 

  8. F. A. Kuehl Jr. and R. W. Egan,Prostaglandins, arachidonic acid, and inflammation. Science.210, 978–984 (1980).

    PubMed  Google Scholar 

  9. S. C. L. Hong and L. Levine,Inhibition of arachidonic acid release from cells and the biochemical action of anti-inflammatory corticosteroids. Proc. Natl. Acad. Sci. USA73, 1730–1734 (1976).

    PubMed  Google Scholar 

  10. J. R. Vane,Inhibition of prostaglandin synthesis as a mechanism of action of aspirin like drugs. Nature New Biol.231, 232–235 (1971).

    PubMed  Google Scholar 

  11. M. E. Loomans, J. A. Miller, R. S. Matthews, R. W. Farmer, D. A. Lade, R. A. Underwood, K. L. Skare and H. H. Tai,The Pharmacology of NE-11740, a new anti-inflammatory agent. 4th Int. Conf. of the Inflammation Research Association, White Haven, PA 23–27 October 1988, Abstract 51.

  12. R. Vargas, F. G. McMahan, A. K. Jain and J. H. Powell,An antipyretic study to determine biological activity of NE-11740 in men. Clin. Pharmacol. Ther.47(2), 163 (1990).

    Google Scholar 

  13. R. M. Kaffenberger, T. H. Eichhold and M. J. Doyle,Determination of Tebufelone (a new anti-inflammatory drug) strength and stability in bulk drug, dosage formulations and feed admixtures by reversed-phase high performance liquid chromatography. J. Chromatogr.505(2), 349–356 (1990).

    Article  PubMed  Google Scholar 

  14. L. H. Rome and W. E. M. LandsProperties of a partiallypurified preparation of the prostaglandin-forming oxygenase from sheep vesicular gland Prostaglandins10(5), 813–824 (1975).

    Article  PubMed  Google Scholar 

  15. C. Y. Li, S. C. Ziesmer, L. T. Yam, M. C. English and A. J. Janckila,Practical immunocytochemical identification of human blood cells. Am. J. Clin Pathol.80, 246–251 (1984).

    Google Scholar 

  16. M. J. Doyle, T. H. Eichhold, B. A. Hynd and S. M. Weisman, Determination of leukotriene B4 in human plasma by gas chromatography using a mass selective detector and a stable isotope labeled internal standard. Effect of NE-11740 on arachidonic acid metabolism, J. Pharmacol. Biomed. Anal.8(2), 137–142 (1990).

    Article  Google Scholar 

  17. T. H. Eichhold and M. J. Doyle,Determination of Tebufelone, a new anti-inflammatory drug, in plasma and tissue using capillary gas chromatography/stable isotope dilution mass spectrometry. Biomed. Environ. Mass Spectrom.19, 230–234 (1990).

    Article  PubMed  Google Scholar 

  18. R. J. Strife, J. R. Simms and M. P. Lacey,Combined capillary gas chromatography/ion trap mass spectrometry quantitative methods using labeled or unlabeled internal standards. J. Amer. Soc. Mass Spectrom.1(3), 265–27 (1990).

    Article  Google Scholar 

  19. R. L. M. Dobson, D. M. Neal, B. R. DeMark and S. R. Ward,Long-term performance of a gas chromatography/tandem mass spectrometry assay for tebufelone in plasma. Anal. Chem.62(17), 1819–1824 (1990).

    Article  PubMed  Google Scholar 

  20. F. J. G. Van der Ouderaa and M. Buytenhek,Purification of PGH Synthase from sheep vesicular glands. Methods. Enzymol.86(9), 60–68 (1982).

    PubMed  Google Scholar 

  21. R. J. Kulmacz and W. E. M. Lands,Prostaglandin H Synthase: Stoichiometry of heme cofactor. J. Biol. Chem.259(4), 6358–6363 (1984).

    PubMed  Google Scholar 

  22. W. H. Rooks II, A. J. Tomolonis, P. J. Maloney, M. B. Wallach and M. E. Schuler,The analgesic and anti-inflammatory profile of (±)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2a]pyrrole-1-carboxylic acid (RS-37619). Agents and Actions12, 684–690 (1982).

    Article  PubMed  Google Scholar 

  23. S. S. Adams, C. A. Burrows, N. Sheldon and D. B. Yates,Inhibition of prostaglandin synthesis and leukocyte migration by flurbiprofen. Curr. Med. Res. Opinion.5(1), 11–16 (1977).

    Google Scholar 

  24. P. Gresele, J. Arnout, M. C. Coene, H. Deckmyn and J. Vermylen, Leukotriene B4 production by stimulated whole blood: Comparative studies with isolated polymorphonuclear cells. Biochem. Biophys. Res. Commun.137(1), 334–342 (1986).

    Article  PubMed  Google Scholar 

  25. M. J. Doyle, T. H. Eichhold, M. E. Loomans, R. W. Farmer and G. R. Kelm,Comparison of Tebufelone distribution in rat blood plasma, and inflamed/non-inflamed tissues following peroral and intravenous dosing. J. Pharmacol. Sci.82(8), 1–4 (1993).

    Google Scholar 

  26. V. D. Rainsford,Current concept of the mechanisms of side effects of nonsterodial anti-inflammatory drugs as a basis for establishing research priorities. AN experimentalist's view. J. Rheumatol.15 (suppl 17), 63–70 (1988).

    Google Scholar 

  27. C. L. Malmsten,Prostaglandis, thromboxanes and leukotrienes in inflammation. Amer. J. Med.80, 11–13 (1986).

    Article  Google Scholar 

  28. O. A. Jakschik, S. Palkhein and C. W. Parker,Precursor role of arachidonic acid in release of slow-reacting substance from rat basophilic leukemia cells. Proc. Natl. Acad. Sci. USA.74, 4577–4581 (1977).

    PubMed  Google Scholar 

  29. S. Sirko, R. Schindler, M. J. Doyle, S. M. Weisman and C. A. Dinarello,Transcription, translation and secretion of interleukin I and tumor necrosis factor: Effects of Tebufelone, a dual cyclooxygenase/5-lipoxygenase inhibitor. Eur. J. Immunol.21, 243–250 (1991).

    PubMed  Google Scholar 

  30. K. Katayama, H. Shirota, S. Kobayashi, K. Terato, H. Ikuta and I. Yamatsu,in vitro effect of N-methoxy-3-(3,5-di-tertbutyl-4-hydroxybenzylidene)-2-pyrrolidone (E-5110), a novel nonsteroidal anti-inflammatory agent, on generation of some inflammatory mediators. Agents and Actions21(314), 269–271 (1987).

    PubMed  Google Scholar 

  31. T. Hidaka, K. Hosoe, Y. Ariki, K. Takeo, T. Yamashita, I. Katsumi, H. Kondo, K. Yamashita and K. Watanabe,Pharmacological properties of a new anti-inflammatory compound, alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), and its inhibitory effects on prostaglandin synthetase and 5-lipoxygenase. Jap. J. Pharmacol.36, 77–85 (1984).

    PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Steven M. Weisman

    Present address: Department of Scientific Affairs, Sterling Winthrop Inc., 90 Park Avenue, 10016, New York, NY, USA

Authors and Affiliations

  1. Miami Valley Laboratories, The Procter & Gamble Company, P.O. Box 398707, 45239-8707, Cincinnati, OH, USA

    Steven M. Weisman, Matthew J. Doyle, Kenneth R. Wehmeyer, Barbara A. Hynd, Thomas H. Eichhold, Rose M. Clear, Chester W. Coggeshall & Debra L. Kuhlenbeck

Authors
  1. Steven M. Weisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew J. Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth R. Wehmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbara A. Hynd
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas H. Eichhold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rose M. Clear
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chester W. Coggeshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Debra L. Kuhlenbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weisman, S.M., Doyle, M.J., Wehmeyer, K.R. et al. Effects of Tebufelone (NE-11740), a new anti-inflammatory drug, on arachidonic acid metabolism. Agents and Actions 41, 156–163 (1994). https://doi.org/10.1007/BF02001910

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02001910

Key words

Search

Navigation