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FPL 62064, a topically active 5-lipoxygenase/cyclooxygenase inhibitor

  • Inflammation and Immunomodulation
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Abstract

FLP 62064 [N-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-3-amine] is a dual inhibitor of prostaglandin synthetase and 5-lipoxygenase. The compound had anti-inflammatory activityin vivo in a number of models. It inhibited peritoneal inflammation induced by immune-complex when given locally. When applied to the skin, FPL 62064 inhibited UV irradiation-induced erythema and PGE2 formation in the guinea pig and also oedema formation and eicosanoid production in the mouse ear produced by arachidonic acid. Co-injected with arachidonic acid in rabbit skin, FPL 62064 inhibited oedema and eicosanoid formation.

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References

  1. C. M. E. Rowland Payne,Psoriatic science. Brit. Med. J195, 1158–1160 (1987).

    Google Scholar 

  2. S. D. Brain, R. D. R. Camp, P. M. Dowd, A. K. Black, P. M. Woollard, A. I. Mallet and M. W. Greaves,Psoriasis and leukotriene B 4. Lancet2, 762–763 (1982).

    Article  Google Scholar 

  3. S. Hammarstrom, M. Hamberg, B. Samuelsson, E. A. Duell, M. Stawiski and J. J. Voorhees,Increased concentrations of non esterified arachidonic acid, 12-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E 2 and prostaglandin F 2 α in epidermis of psoriasis. Proc. Nat. Acad. Sci. USA72, 5130–5134 (1975).

    PubMed  Google Scholar 

  4. A. Blackham, R. J. Griffiths, A. A. Norris, B. E. Wood, S. W. Li, C. Hallam, P. D. Mitchell and J. Mann,FPL 62064: A novel dual inhibitor of arachidonic acid metabolism in skin. Brit. J. Pharmacol.95, 536P, (1988).

  5. F. B. Ubatuba and S. Moncada,Enzymatic preparation of prostaglandin endoperoxides. Prostaglandins13, 1055–1066 (1977).

    Article  PubMed  Google Scholar 

  6. I. Kimura, Y. Moritani and T. Tanizaki,Basophils in bronchial asthma with reference to reagin-type allergy. Clin. Allergy3, 195–202 (1973).

    PubMed  Google Scholar 

  7. B. A. Jakschik, S. Falkenhein, and C. W. Parker,Precursor role of arachidonic acid in release of slow reacting substance from rat basophilic leukaemia cells. Proc. Natl. Acad. Sci. USA74, 4577–4581 (1977).

    PubMed  Google Scholar 

  8. H. H. Bergmeyer,Methods of Enzymatic Analysis p736, Academic Press, (1965).

  9. P. B. Bradley, D. A. Priebat, R. D. Christensen and G. Rothstein,Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker. J. Invest. Dermatol.78, 206–209 (1982).

    Article  PubMed  Google Scholar 

  10. R. J. Griffiths, B. E. Wood, S. W. Li and A. Blackham,Pharmacological modification of 12-O-tetradecanoylphorbol-13-acetate induced inflammation and epidermal cell proliferation in mouse skin. Agents and Actions25 (3/4) 344–351 (1988).

    PubMed  Google Scholar 

  11. A. Blackham and F. A. M. Woods,Immune complex mediated inflammation in the mouse peritoneal cavity. J. Pharm Method15, 77–85 (1986).

    Article  Google Scholar 

  12. H. S. Penefsky,Reversible binding of P i by beef heart mitochondrial adenosine triphosphatase. J. Biol. Chem.252, 2891–2899 (1977).

    PubMed  Google Scholar 

  13. R. A. Appleton, J. R. Bantick, S. C. Burford, N. P. Gensmantel, D. N. Hardern, S. Hill and D. P. Marriot,Derivatives of 1-phenylpyrazol-3-amine: novel inhibitors of 5-lipoxygenase. The 4th SCI-RSC Med. Chem. Sym. Cambridge, p. 1 (1987).

  14. R. W. Egan, A. N. Tischler, E. M. Baptista, E. A. Ham, D. N. Sonderman and P. H. Gale,Specific inhibition and oxidative regulation of 5-lipoxygenase. Adv. Prostagl. Thrombox. Leukotriene Res.11, 151–157 (1983).

    Google Scholar 

  15. E. J. Corey,Enzymic lipoxygenation of arachidonic acid: mechanism, inhibition, and role in eicosanoid biosynthesis. Pure Appl. Chem.59, 269–278 (1987).

    Google Scholar 

  16. R. W. Egan and P. H. Gale,Inhibition of mammalian 5-lipoxygenase by aromatic disulphides. J. Biol. Chem.260, 11554–11559 (1985).

    PubMed  Google Scholar 

  17. J. M. Young, D. A. Spires, C. J. Bedord, B. Wagner, S. J. Ballaron and L. M. de Young,The mouse ear inflammatory response to topical arachidonic acid. J. Invest. Dermatol.82, 367–371 (1984).

    Article  PubMed  Google Scholar 

  18. E. E. Opas, R. J. Bonney and J. L. Humes,Prostaglandin and leukotriene synthesis in mouse ears inflamed by arachidonic acid. J. Invest. Dermatol.84, 253–256 (1985).

    Article  PubMed  Google Scholar 

  19. R. P. Carlson, L. O'Neill-Davis, J. Chang and A. J. Lewis,Modulation of mouse ear oedema by cyclooxygenase and lipoxygenase inhibitors and other pharmacologic agents. Agents and Actions17, 197–204 (1985).

    Article  PubMed  Google Scholar 

  20. D. M. Aked, S. J. Foster, A. Howarth, M. E. McCormick and H. C. Potts,The inflammatory response of rabbit skin to topical arachidonic acid and its pharmacological modulation. Brit. J. Pharmac.89, 431–438 (1986).

    Google Scholar 

  21. D. M. Aked and S. I. Foster,Leukotriene B 4 and prostaglandin E 2 mediate the inflammatory response of rabbit skin to intradermal arachidonic acid. Brit. J. Pharmac.92, 545–552 (1987).

    Google Scholar 

  22. A. Fournier and A. W. Murray,Application of phorbol ester to mouse skin causes a rapid and sustained loss of protein kinase C. Nature330, 767–769 (1987).

    Article  PubMed  Google Scholar 

  23. M. Gschwendt, W. Kittstein, F. Horn and F. Marks,Cyclosporin A inhibits biological effects of tumour promoting phorbol esters. Biochem. biophys. Res. Comm.126, 327–332 (1985).

    Article  PubMed  Google Scholar 

  24. B. Dawson, R. L. Follenfant, G. A. Higgs, C. Schneider and J. R. Gibson,The effect of BW 540C, a novel anti-inflammatory agent, on ultraviolet-induced physical and histological changes in guinea-pig skin. Brit. J. Dermatol.113, (suppl. 28), 137–140 (1985).

    Google Scholar 

  25. A. Blackham, A. A. Norris and the late F. A. M. Woods,Models for evaluating the anti-inflammatory effects of inhibitors of arachidonic acid metabolism. J. Pharm. Pharmacol.37, 787–793 (1985).

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry, Fisons plc-Pharmaceutical Division, Bakewell Road, LE11 0RH, Loughborough, Leicestershire, UK

    A. Blackham, R. J. Griffiths, C. Hallam,  J. Mann, P. D. Mitchell, A. A. Norris & W. T. Simpson

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  1. A. Blackham
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  2. R. J. Griffiths
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  3. C. Hallam
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  4. J. Mann
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  5. P. D. Mitchell
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  6. A. A. Norris
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  7. W. T. Simpson
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Blackham, A., Griffiths, R.J., Hallam, C. et al. FPL 62064, a topically active 5-lipoxygenase/cyclooxygenase inhibitor. Agents and Actions 30, 432–442 (1990). https://doi.org/10.1007/BF01966309

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  • DOI: https://doi.org/10.1007/BF01966309

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