EFFECTS OF TEBUFELONE (NE-11740), A NEW ANTIINFLAMMATORY 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-infla mmatory, 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 formati on of prostaglandins (PGE(2)) a key mediator of pain and inflammation, in isolated enzyme preparations (IC50 = 1.5 mu M, K-I = 0.35 mu M), t wo in vitro cellular systems: rat peritoneal macrophages (IC50 = 0.02 mu M) and human whole blood (IC50 = 0.08 mu M), and ex vivo in man. In addition to PGE(2) inhibition, which is common to all NSAIDs, higher concentrations of Tebufelone block the in vitro formation of products of the lipoxygenase pathway [leukotrienes (LTB(4))] in rat macrophages (IC50 = 20 mu M) and human whole blood (IC50 = 22 mu M). Substrate in corporation studies (C-14-AA) indicate that Tebufelone reversibly inhi bits cyclooxygenase (CO) and 5-lipoxygenase (5-LO) enzymes rather than regulating the release of AA. Tebufelone was shown to be a more poten t CO inhibitor than indomethacin and a less potent 5-LO inhibitor than RG-5901. Comparisons to structurally related compounds under developm ent (E-5110, Esai; KME-4, Kanagafuchi), found Tebufelone to be the mos t potent CO inhibitor in vitro. All three DTBP compounds were equipote nt 5-LO inhibitors. It is likely that Tebufelone's inhibitory effects on AA metabolism are, in part, responsible for its in vivo efficacy an d enhanced safety profile.