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. 1991 Jan 15;88(2):355–359. doi: 10.1073/pnas.88.2.355

N-(fluorenyl-9-methoxycarbonyl) amino acids, a class of antiinflammatory agents with a different mechanism of action.

R M Burch 1, M Weitzberg 1, N Blok 1, R Muhlhauser 1, D Martin 1, S G Farmer 1, J M Bator 1, J R Connor 1, M Green 1, C Ko 1, et al.
PMCID: PMC50809  PMID: 1824872

Abstract

Several members of a series of N-(fluorenyl-9-methoxycarbonyl) amino acids were found to possess a broad spectrum of antiinflammatory activity. The compounds were active against oxazolone dermatitis in mice and adjuvant arthritis in rats, models in which activated T lymphocytes are implicated. The compounds also inhibited T-lymphocyte activation in vitro, assessed by using the mixed lymphocyte reaction. The compounds inhibited the reversed passive Arthus reaction in rats and arachidonic acid-induced dermatitis in mice, models in which leukocyte infiltration is responsible for the inflammatory reaction. More complete evaluation was made of one compound, N-(fluorenyl-9-methoxycarbonyl)leucine (NPC 15199). On histologic examination after arachidonic acid administration, NPC 15199 was found to block recruitment of neutrophils into the inflammatory site. The compound was not a general myelotoxin. Prolonged treatment of animals did not alter bone-marrow progenitor number or the numbers of circulating white blood cells. Further, several white cell functions were not inhibited in vitro, including neutrophil respiratory burst and macrophage phagocytosis. NPC 15199 was effective in blocking antigen arthritis in rabbits and was effective in a therapeutic protocol, reversing oxazolone edema. These studies suggest that N-(fluorenyl-9-methoxycarbonyl) amino acids may be valuable therapeutic agents for inflammatory diseases.

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Selected References

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  1. Aksamit R. R., Falk W., Leonard E. J. Chemotaxis by mouse macrophage cell lines. J Immunol. 1981 Jun;126(6):2194–2199. [PubMed] [Google Scholar]
  2. Besedovsky H. O., del Rey A., Sorkin E. Lymphokine-containing supernatants from con A-stimulated cells increase corticosterone blood levels. J Immunol. 1981 Jan;126(1):385–387. [PubMed] [Google Scholar]
  3. Bräuer R., Thoss K., Henzgen S., Waldmann G. Significance of cell-mediated and humoral immunity in the acute and chronic phase of antigen-induced arthritis in rabbits. Exp Pathol. 1988;34(4):197–208. doi: 10.1016/s0232-1513(88)80151-8. [DOI] [PubMed] [Google Scholar]
  4. Burch R. M., Connor J. R., Axelrod J. Interleukin 1 amplifies receptor-mediated activation of phospholipase A2 in 3T3 fibroblasts. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6306–6309. doi: 10.1073/pnas.85.17.6306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chang Y. H., Otterness I. G. Effects of pharmacologic agents on the reversed passive Arthus reaction in the rat. Eur J Pharmacol. 1981 Jan 16;69(2):155–164. doi: 10.1016/0014-2999(81)90410-6. [DOI] [PubMed] [Google Scholar]
  6. DUMONDE D. C., GLYNN L. E. The production of arthritis in rabbits by an immunological reaction to fibrin. Br J Exp Pathol. 1962 Aug;43:373–383. [PMC free article] [PubMed] [Google Scholar]
  7. Naito K., Komatsubara S., Kawai J., Mori K., Muramatsu S. Role of macrophages as modulators but not as stimulators in primary mixed leukocyte reaction. Cell Immunol. 1984 Oct 15;88(2):361–373. doi: 10.1016/0008-8749(84)90169-2. [DOI] [PubMed] [Google Scholar]
  8. Selvaraj R. J., Sbarra A. J., Thomas G. B., Cetrulo C. L., Mitchell G. W., Jr A microtechnique for studying chemiluminescence response of phagocytes using whole blood and its application to the evaluation of phagocytes in pregnancy. J Reticuloendothel Soc. 1982 Jan;31(1):3–16. [PubMed] [Google Scholar]
  9. Taurog J. D., Argentieri D. C., McReynolds R. A. Adjuvant arthritis. Methods Enzymol. 1988;162:339–355. doi: 10.1016/0076-6879(88)62089-1. [DOI] [PubMed] [Google Scholar]
  10. Taurog J. D., Kerwar S. S., McReynolds R. A., Sandberg G. P., Leary S. L., Mahowald M. L. Synergy between adjuvant arthritis and collagen-induced arthritis in rats. J Exp Med. 1985 Sep 1;162(3):962–978. doi: 10.1084/jem.162.3.962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Young J. M., Spires D. A., Bedord C. J., Wagner B., Ballaron S. J., De Young L. M. The mouse ear inflammatory response to topical arachidonic acid. J Invest Dermatol. 1984 Apr;82(4):367–371. doi: 10.1111/1523-1747.ep12260709. [DOI] [PubMed] [Google Scholar]
  12. Young J. M., Wagner B. M., Spires D. A. Tachyphylaxis in 12-0-tetradecanoylphorbol acetate- and arachidonic acid-induced ear edema. J Invest Dermatol. 1983 Jan;80(1):48–52. doi: 10.1111/1523-1747.ep12531048. [DOI] [PubMed] [Google Scholar]

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