Weisman S M, Doyle M J, Wehmeyer K R, Hynd B A, Eichhold T H, Clear R M, Coggeshall C W, Kuhlenbeck D L
Proctor & Gamble Company, Miami Valley Laboratories, Cincinnati, OH 45239-8707.
Agents Actions. 1994 May;41(3-4):156-63. doi: 10.1007/BF02001910.
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.
替布非隆是一种新型非甾体抗炎药（NSAID），属于二叔丁基苯酚（DTBP）类，在多种动物模型中显示出强效的抗炎、镇痛和解热特性。在本报告中，对替布非隆对花生四烯酸（AA）代谢的影响进行了综述。替布非隆在离体酶制剂（IC50 = 1.5微摩尔，KI = 0.35微摩尔）、两种体外细胞系统：大鼠腹腔巨噬细胞（IC50 = 0.02微摩尔）和人全血（IC50 = 0.08微摩尔）以及人体离体实验中，能有效抑制前列腺素（PGE2）的形成，PGE2是疼痛和炎症的关键介质。除了抑制PGE2（这是所有NSAIDs的共同作用）外，更高浓度的替布非隆还能阻断大鼠巨噬细胞（IC50 = 20微摩尔）和人全血（IC50 = 22微摩尔）中脂氧合酶途径产物[白三烯（LTB4）]的体外形成。底物掺入研究（14C - AA）表明，替布非隆可逆性抑制环氧化酶（CO）和5 - 脂氧合酶（5 - LO），而不是调节AA的释放。已证明替布非隆是比吲哚美辛更强效的CO抑制剂，比RG - 5901更弱效的5 - LO抑制剂。与正在研发的结构相关化合物（E - 5110，卫材株式会社；KME - 4，金泽制药）比较发现，替布非隆是体外最有效的CO抑制剂。所有三种DTBP化合物都是等效的5 - LO抑制剂。替布非隆对AA代谢的抑制作用可能部分是其体内疗效和安全性提高的原因。
