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

Ronald M. Burch, Moshe Weitzberg, Natalie Blok, Richard Muhlhauser, David Martin, Stephen G. Farmer, Jenny M. Bator, Jane R. Connor, Chiew Ko, Wendy Kuhn, Barbara A. McMillan, Maureen Raynor, Barry G. Shearer, Carol W Tiffany, Deidre E. Wilkins

Research output: Contribution to journalArticle

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 on which leukocyte infiltration is responsible for 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 resiratory 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
Volume88
Issue number2
StatePublished - 1991

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Anti-Inflammatory Agents
Oxazolone
Amino Acids
Dermatitis
Arachidonic Acid
Leukocytes
Arthus Reaction
T-Lymphocytes
Mixed Lymphocyte Culture Test
Experimental Arthritis
Neutrophil Infiltration
Lymphocyte Activation
Phagocytosis
Arthritis
Edema
Neutrophils
Bone Marrow
Macrophages
Rabbits
Antigens

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

N-(Fluorenyl-9-methoxycarbonyl) amino acids, a class of antiinflammatory agents with a different mechanism of action. / Burch, Ronald M.; Weitzberg, Moshe; Blok, Natalie; Muhlhauser, Richard; Martin, David; Farmer, Stephen G.; Bator, Jenny M.; Connor, Jane R.; Ko, Chiew; Kuhn, Wendy; McMillan, Barbara A.; Raynor, Maureen; Shearer, Barry G.; Tiffany, Carol W; Wilkins, Deidre E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 88, No. 2, 1991, p. 355-359.

Research output: Contribution to journalArticle

Burch, RM, Weitzberg, M, Blok, N, Muhlhauser, R, Martin, D, Farmer, SG, Bator, JM, Connor, JR, Ko, C, Kuhn, W, McMillan, BA, Raynor, M, Shearer, BG, Tiffany, CW & Wilkins, DE 1991, 'N-(Fluorenyl-9-methoxycarbonyl) amino acids, a class of antiinflammatory agents with a different mechanism of action', Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 2, pp. 355-359.
Burch, Ronald M. ; Weitzberg, Moshe ; Blok, Natalie ; Muhlhauser, Richard ; Martin, David ; Farmer, Stephen G. ; Bator, Jenny M. ; Connor, Jane R. ; Ko, Chiew ; Kuhn, Wendy ; McMillan, Barbara A. ; Raynor, Maureen ; Shearer, Barry G. ; Tiffany, Carol W ; Wilkins, Deidre E. / N-(Fluorenyl-9-methoxycarbonyl) amino acids, a class of antiinflammatory agents with a different mechanism of action. In: Proceedings of the National Academy of Sciences of the United States of America. 1991 ; Vol. 88, No. 2. pp. 355-359.
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