Effects of tebufelone (NE-11740), a new anti-inflammatory drug, on arachidonic acid metabolism

Tebufelone is a novel nonsteroidal anti-inflammatory drug (NSAID), of the di-tert-butylphenol (DTBP) class, which displays potent anti-inflammatory, analgesic and anti-pyretic properties in a variety of animal models. In this report, the effects of Tebufelone on arachidonic acid (AA) metabolism are...

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Bibliographic Details
Published in:Agents and Actions 1994-05, Vol.41 (3-4), p.156-163
Main Authors: Weisman, S M, Doyle, M J, Wehmeyer, K R, Hynd, B A, Eichhold, T H, Clear, R M, Coggeshall, C W, Kuhlenbeck, D L
Format: Article
Language:English
Subjects:
Alkynes - pharmacology
Alkynes - therapeutic use
Animals
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Anti-Inflammatory Agents, Non-Steroidal - therapeutic use
Arachidonic Acid - metabolism
Calcimycin - pharmacology
Cyclooxygenase Inhibitors - pharmacology
Dinoprostone - antagonists & inhibitors
Humans
Indomethacin - pharmacology
Leukotriene B4 - blood
Lipoxygenase Inhibitors
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - metabolism
Male
Phenols - pharmacology
Phenols - therapeutic use
Prostaglandin-Endoperoxide Synthases - metabolism
Quinolines - pharmacology
Rats
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Summary:Tebufelone is a novel nonsteroidal anti-inflammatory drug (NSAID), of the di-tert-butylphenol (DTBP) class, which displays potent anti-inflammatory, analgesic and anti-pyretic properties in a variety of animal models. In this report, the effects of Tebufelone on arachidonic acid (AA) metabolism are reviewed. Tebufelone potently inhibits the formation of prostaglandins (PGE2) a key mediator of pain and inflammation, in isolated enzyme preparations (IC50 = 1.5 microM, KI = 0.35 microM), two in vitro cellular systems: rat peritoneal macrophages (IC50 = 0.02 microM) and human whole blood (IC50 = 0.08 microM), and ex vivo in man. In addition to PGE2 inhibition, which is common to all NSAIDs, higher concentrations of Tebufelone block the in vitro formation of products of the lipoxygenase pathway [leukotrienes (LTB4)] in rat macrophages (IC50 = 20 microM) and human whole blood (IC50 = 22 microM). Substrate incorporation studies (14C-AA) indicate that Tebufelone reversibly inhibits cyclooxygenase (CO) and 5-lipoxygenase (5-LO) enzymes rather than regulating the release of AA. Tebufelone was shown to be a more potent CO inhibitor than indomethacin and a less potent 5-LO inhibitor than RG-5901. Comparisons to structurally related compounds under development (E-5110, Esai; KME-4, Kanagafuchi), found Tebufelone to be the most potent CO inhibitor in vitro. All three DTBP compounds were equipotent 5-LO inhibitors. It is likely that Tebufelone's inhibitory effects on AA metabolism are, in part, responsible for its in vivo efficacy and enhanced safety profile.
ISSN:0065-4299
1420-908X
DOI:10.1007/BF02001910