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

R. M. Burch, M. Weitzberg, N. Blok, R. Muhlhauser, D. Martin, S. G. Farmer, J. M. Bator, J. R. Connor, C. Ko, W. Kuhn, B. A. McMillan, M. Raynor, B. G. Shearer, C. Tiffany, D. E. Wilkins

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)355-359
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
StatePublished - 1991
Externally publishedYes

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