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Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228: Impact upon Leukotriene B4- and 12(R)-HETE- mediated events

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Abstract

Leukotriene B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 {7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid}, a first-generation LTB4 receptor antagonist, inhibited the chemotactic actions of LTB4 when given orally with an ED50 value of 1.7 mg/kg. The second-generation LTB4 receptor antagonist, SC-53228 [(+)-(S)-7-(3-{2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy} propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid], inhibited LTB4-induced chemotaxis when given intragastrically with an ED50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED50 value of 5.8 mg/kg. When dosed orally over a range of 0.03–100 mg/kg, SC-53228 gaveC max plasma concentrations of 0.015–41.1μg/ml. SC-53228 inhibited LTB4-primed membrane depolarization of human neutrophils with an IC50 value of 34 nM. As a potent LTB4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB4 and/or 12(R)-HETE are implicated as inflammatory mediators.

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References

  1. Palmblad, J., C. Malmsten, A. Uden, O. Radmark, L. Engstrot, andB. Samuelsson. 1981. Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence.Blood 58:658–661.

    PubMed  Google Scholar 

  2. Redl, H., P. Flynn, H. Lamche, A. Schiesser, G. Schlag, andD. Hammerschmidt. 1983. Aggregation, chemotaxis and chemiluminescence of canine granulocytes.Inflammation 7:67–79.

    PubMed  Google Scholar 

  3. Ford-Hutchinson, A., M. Bray, M. Doug, M. Shipley, andM. Smith. 1980. Leukotriene B4, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes.Nature 286:264–265.

    PubMed  Google Scholar 

  4. Hoover, R., M. Karnovsky, K. Austin, E. Corey, andR. Lewis. 1984. Leukotriene B4 action on endothelium mediates augmented neutrophil/endothelial adhesion.Proc. Natl. Acad. Sci. U.S.A 81:2191.

    PubMed  Google Scholar 

  5. Czarnetzki, B., andR. Mertensmeir. 1985. In vitro and in vivo chemotaxis of guinea pig leukocytes toward leukotriene B4 and itsω-oxidation products.Prostaglandins 30:5–11.

    PubMed  Google Scholar 

  6. Colditz, I., andH. Movat. 1984. Kinetics of neutrophil accumulation in acute inflammatory lesions induced by chemotaxis and chemotaxiningens.J. Immunol. 133:2169–2173.

    PubMed  Google Scholar 

  7. Bhattacherjee, P., B. Hammond, J. Salmon, R. Stepney, andK. Eakins. 1981. Chemotactic response to some arachidonic acid lipoxygenase products in the rabbit eye.Eur. J. Pharmacol. 73:21–28.

    PubMed  Google Scholar 

  8. Camp, R., A. Coutts, M. Greaves, A. Kay, andM. Walport. 1983. Responses of human skin to intradermal injection of leukotrienes C4, D4, and B4.Br. J. Pharmacol. 8:497–502.

    Google Scholar 

  9. Soter, N., R. Lewis, E. Corey, andK. W. Austin. 1983. Local effects of synthetic leukotrienes (LTC4, LTD4, and LTB4) in human skin.J. Invest. Dermatol. 80:115–119.

    PubMed  Google Scholar 

  10. DeJong, E. M. G. J., P. E. G. van Erp, I. M. J. J. van Vlijmen, andP. C. M. van der Kerkhof. 1991. Cutaneous inflammation and proliferation induced by leukotriene B4.In Immunological and Pharmacological Aspects of Atopic and Contact Eczema. J. Czernielewski, editor. Karger, Basel, 72–75.

    Google Scholar 

  11. Kragballe, K., L. Desjarlais, andJ. J. Voorhees. 1985. Leukotriene B4, C4 and D4 stimulate DNA synthesis in cultured human epidermal keratinocytes.Br. J. Dermatol. 113:43–52.

    PubMed  Google Scholar 

  12. Palmblad, J., R. Lerner, andS. H. Larsson. 1994. Signal transduction mechanism for LTB4-induced hyperadhesiveness of endothelial cells for neutrophils.J. Immunol. 152:262–269.

    PubMed  Google Scholar 

  13. Yamaoka, K. A., andJ.-P. Kolb. 1993. Leukotriene B4 induces interleukin 5 generation from human T-lymphocytes.Eur. J. Immunol. 23:2392–2398.

    PubMed  Google Scholar 

  14. Cunningham, F. M., andP. M. Woolard. 1987. 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid is a chemoattractant for human polymorphonuclear leukocytes in vitro.Prostaglandins 34:71–78.

    PubMed  Google Scholar 

  15. Fogh, K., J. Kiil, T. Herlin, T. H. Ternowitz, andK. Kragballe. 1987. Heterogeneous distribution of lipoxygenase products in psoriatic skin lesions.Arch. Dermatol. Res. 279:504–511.

    PubMed  Google Scholar 

  16. Woolard, P. M. 1986. Stereochemical difference between 12-hydroxy-5,8,10,14-eicosatetraenoic acid in platelets and psoriatic lesions.Biochem. Biophys. Res. Commun. 136:169–176.

    PubMed  Google Scholar 

  17. Woolard, P. M., G. M. Murphy, F. M. Cunningham, R. D. R. Camp, andM. W. Greaves. 1988. Proinflammatory effects of 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid in human skin.Br. J. Dermatol. 118:277.

    Google Scholar 

  18. Evans, J. F., Y. Leblanc, B. J. Fitzsimmons, S. Charleson, D. Nathaniel, andC. Leveille. 1987. Activation of leukocyte movement and displacement of [3H]leukotriene-B4from leukocyte membrane preparations by 12(R)- and 12(S)-hydroxyeicosatetraenoic acid.Biochim. Biophys. Acta 917:406–410.

    PubMed  Google Scholar 

  19. Cunningham, F. M., P. M. Woolard, andR. D. R. Camp. 1985. Proinflammatoty properties of unsaturated fatty acids and their monohydroxy metabolites.Prostaglandins 30:497–509.

    PubMed  Google Scholar 

  20. Keith, R., W. Smith, B. Tsai, S. Levin, andG. Butchko. 1985. Myeloperoxidase activity in experimentally induced colitis.Fed. Proc. 44:1545.

    Google Scholar 

  21. Krawisz, J., P. Sharon, andW. Stenson. 1984. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity.Gastroenterology 87:1344–1350.

    PubMed  Google Scholar 

  22. Bradley, P., D. Priebat, R. Christensen, andG. Rothstein. 1982. Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker.J. Invest. Dermatol. 78:206–209.

    PubMed  Google Scholar 

  23. Fretland, D., S. Levin, B. Tsai, S. Djuric, D. Widomski, J. Zemaitis, R. Shone, andR. Bauer. 1989. The effect of a leukotriene-B4 receptor antagonist, SC-41930, on acetic acidinduced colonic inflammation.Agents Actions 27:225–227.

    Google Scholar 

  24. Fretland, D., D. Widomski, J. Zemaitis, R. Walsh, S. Levin, S. Djuric, R. Shone, B. C. Tsai, andT. Gaginella 1990. Inflammation of guinea pig dermis: effects of leukotriene B4 receptor antagonist SC-41930.Inflammation 14:727–739.

    PubMed  Google Scholar 

  25. Fretland, D., D. Widomski, B. Tsai, J. Zemaitis, S. Levin, S. Djuric, R. Shone, andT. Gaginella. 1990. Effect of the leukotriene B4 receptor antagonist SC-41930 on colonic inflammation in rat, guinea pig and rabbit.J. Pharmacol. Exp. Ther. 255:572–576.

    PubMed  Google Scholar 

  26. Djuric, S. W., S. H. Docter, S. S. Yu, B. S. Tsai, C. P. Anglin, T. S. Gaginella, J. F. Kachur, R. H. Keith, T. J. Maziasz, D. Price, T. Rao, R. E. Walsh, D. L. Widomski, andD. J. Fretland. 1994. Synthesis and pharmacological activity of SC-53228, a leukotriene B4 receptor antagonist with high intrinsic potency and selectivity.Biorg. Med. Chem. Lett. 4:811–816.

    Google Scholar 

  27. Fretland, D. J., D. L. Widomski, C. P. Anglin, T. D. Penning, S. Yu, andS. W. Djuric. 1993. Leukotriene B4-induced granulocyte trafficking in guinea pig dermis: Effect of the second-generation LTB4 receptor antagonists, SC-50605 and SC-51146.Inflammation 17:353–360.

    PubMed  Google Scholar 

  28. Tsai, B., R. Keith, D. Price, J. Kachur, D. Yang, S. Djuric, andS. Yu. 1994. The in vitro pharmacology of SC-51146: A potent antagonist of LTB4 receptors.J. Pharamcol. Exp. Ther. 268:1499–1505.

    Google Scholar 

  29. Fretland, D., D. Widomski, J. Zemaitis, S. Djuric, andR. Shone. 1989. Effect of a leukotriene B4 receptor antagonist on leukotriene B4-induced neutrophil chemotaxis in cavine dermis.Inflammation 13:601–605.

    PubMed  Google Scholar 

  30. Fretland, D. J., D. L. Widomski, J. M. Zemaitis, B. S. Tsai, S. W. Djuric, T. D. Penning, J. M. Miyashiro, andR. F. Bauer. 1989. 12(R)-Hydroxyeicosatetraenoic acid is a neutrophil chemoattractant in the cavine, lapine, murine and canine dermis.Prostaglandins Leukotrienes Essent. Fatty Acids 37:79–81.

    Google Scholar 

  31. Smith, W., B. Cohen, S. Levin, andG. Butchko. 1986. In vivo chemotaxis to leukotriene B4 detected by myeloperoxidase activity.Fed. Proc. 45:63.

    Google Scholar 

  32. Borgeat, P., andP. H. Naccache. 1990. Biosynthesis and biological activity of leukotriene B4.Clin. Biochem. 23:459–468.

    PubMed  Google Scholar 

  33. Fretland, D., D. Widomski, C. Anglin, S. Yu, andS. W. Djuric. 1992. Optical isomers of a leukotriene B4 antagonist have differential effects on granulocyte diapedesis in the guinea pig dermis.Chirality 4:1–3.

    PubMed  Google Scholar 

  34. Fretland, D. J., D. L. Widomski, R. L. Shone, T. D. Penning, J. M. Miyashiro, andS. W. Djuric. 1989. SC-41930 inhibits neutrophil infiltration of the cavine dermis induced by 12(R)-hydroxyeicosatetraenoic acid.Prostaglandins Leukotrienes Essent. Fatty Acids 38:169–172.

    Google Scholar 

  35. Di Martino, M., C. E. Wolff, G. Campbell, andN. Hanna. 1989. The pharmacology of arachidonic acid-induced rat PMN leukocyte infiltration.Agents Actions 27:325–327.

    PubMed  Google Scholar 

  36. Boughton-Smith, N. K., J. L. Wallace, andB. J. R. Whittle. 1988. Relationships between arachidonic acid metabolism, myeloperoxidase activity and leukocyte infiltration in a rat model of inflammatory bowel disease.Agents Actions 25:115–123.

    PubMed  Google Scholar 

  37. Sharon, P., andW. F. Stenson. 1984. Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease.Gastroenterology 86:453–460.

    PubMed  Google Scholar 

  38. Stenson, W. F. 1988. Arachidonic acid metabolites in inflammatory bowel disease.Adv. Inflam. Res 12:215–222.

    Google Scholar 

  39. Stenson, W. F. 1988. Leukotriene B4 in inflammatory bowel disease.In Inflammatory Bowel Diseases. H. Goebell, editor. MTP press, Lancaster, U.K. 143–152.

    Google Scholar 

  40. Ziboh, V., T. Casebolt, C. Marcelo, andJ. Voorhees. 1984. Biosynthesis of lipoxygenase products by enzyme preparations from normal and psoriatic skin.J. Invest. Dermatol. 83:426–430.

    PubMed  Google Scholar 

  41. Brain, S., R. Camp, P. Dowd, A. Kobza-Black, andM. Greaves. 1984. The release of leukotriene-B4-like material in biologically active amounts from the lesional skin of patients with psoriasis.J. Invest. Dermatol. 83:70–73.

    PubMed  Google Scholar 

  42. Fretland, D. J., andS. W. Djuric. 1989. 12(R)- and 12(S)-Hydroxyeicosatetraenoic acids: chemistry, biology, and pharmacology.Prostaglandins Leukotrienes Essent. Fatty Acids 38:215–228.

    Google Scholar 

  43. Kragballe, K., L. Desjarlais, E. A. Duell, andJ. J. Voorhees. 1986. In vitro synthesis of 12-hydroxyeicosatetraenoic acid is increased in uninvolved psoriatic epidermis.J. Invest. Dermatol. 87:47–52.

    PubMed  Google Scholar 

  44. Grob, E., T. Ruzicka, C. Mauch, andT. Krieg. 1988. Evidence for LTB4/12-HETE binding sites in a human epidermal cell line.Prostaglandins 36:49–58.

    PubMed  Google Scholar 

  45. Barr, R., S. Brain, R. D. R. Camp, F. F. Derm, J. Cilliers, M. W. Greaves, A. Mauet, andK. Misch. 1984. Levels of arachidonic acid metabolites in the skin in human allergic and irritant contact dermatitis.Br. J. Dermatol. 111:23–28.

    PubMed  Google Scholar 

  46. Ruzicka, T., T. Simmet, andB. A. Peskar. 1986. Skin levels of arachidonic acid-derived inflammation mediators and histamine in atopic dermatitis and psoriasis.J. Invest. Dermatol. 86:105–108.

    PubMed  Google Scholar 

  47. Williams, T. J., A. Das, C. von Vexkull, andS. Nourshargh. 1991. Neutrophils in asthma.Ann. NY Acad. Sci. 629:73–81.

    PubMed  Google Scholar 

  48. O'Byrne, P. M. 1990. Eicosanoids and inflammatory cells in asthma.Agents Actions Suppl. 31:85–101.

    PubMed  Google Scholar 

  49. Calhoun, W., J. Sedgwick, andW. Busse. 1991. The role of eosinophils in the pathophysiology of asthma.Ann. NY Acad. Sci. 629:62–72.

    PubMed  Google Scholar 

  50. Lucchesi, B., andK. Mullane. 1986. Leukocytes and ischemia-induced myocardial injury.Annu. Rev. Toxicol. 26:201–224.

    Google Scholar 

  51. Mullane K. 1988. Eicosanoids in myocardial ischemia/reperfusion injury.Adv. Inflammation Res. 12:191–214.

    Google Scholar 

  52. Zimmerman, B., D. Guillory, M. Grisham, T. Gaginella, J. Mallarkey, andD. N. Granger. 1990. Role of leukotriene B4 in granulocyte infiltration into the postischemic feline intestine.Gastroenterology 99:1358–1363.

    PubMed  Google Scholar 

  53. Ahmadzadeh, N., M. Shingu, U. Sosumi, M. Nobunaga, andT. Tawara. 1991. Relationship between leukotriene B4 and immunological parameters in rheumatoid synovial fluids.Inflammation 15:497–503.

    PubMed  Google Scholar 

  54. Spurney, R. F., S. Ibrahim, D. Butterfly, P. E. Klotman, F. Sanfilippo, andT. M. Coffman. 1994. Leukotrienes in renal transplant rejection in rats.J. Immunol. 152:867–876.

    PubMed  Google Scholar 

  55. Konstan, M. W., R. W. Walenga, K. A. Hilliard, andJ. B. Hilliard. 1993. Leukotriene-B4 markedly elevated in the epithelial lining fluid of patients with cystic fibrosis.Am. Rev. Respir. Dis. 148:896–901.

    PubMed  Google Scholar 

  56. Djuric, S. W., D. J. Fretland, andT. D. Penning. 1992. The leukotriene B4 receptor antagonists—a most discriminating class of antiinflammatory agents?.Drugs Future 17:819–830.

    Google Scholar 

  57. Ziboh, V. A. 1994. Essential fatty acids and eicosanoid biosynthesis in the skin: Biological significance.Proc. Soc. Exp. Biol. Med. 205:1–11.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Inflammatory Diseases Research, Searle Research and Development, Chesterfield, Missouri

    D. J. Fretland, C. P. Anglin, M. Bremer, P. Isakson, D. L. Widomski & J. P. McKearn

  2. Department of Pharmacokinetics, Bioanalytical and Radiochemistry, Searle Research and Development, Chesterfield, Missouri

    S. K. Paulson

  3. Department of Medicinal Chemistry, Searle Research and Development, Chesterfield, Missouri

    S. H. Docter, S. W. Djuric, T. D. Penning & S. Yu

  4. 4901 Searle Parkway, 60077, Skokie, Illinois

    D. J. Fretland, C. P. Anglin, M. Bremer, P. Isakson, D. L. Widomski, S. K. Paulson, S. H. Docter, S. W. Djuric, T. D. Penning, S. Yu & J. P. McKearn

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Fretland, D.J., Anglin, C.P., Bremer, M. et al. Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228: Impact upon Leukotriene B4- and 12(R)-HETE- mediated events. Inflammation 19, 193–205 (1995). https://doi.org/10.1007/BF01534461

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