Boschelli D H, Connor D T, Bornemeier D A, Dyer R D, Kennedy J A, Kuipers P J, Okonkwo G C, Schrier D J, Wright C D
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106-1047.
J Med Chem. 1993 Jun 25;36(13):1802-10. doi: 10.1021/jm00065a002.
N-Arylanthranilic acids, known generically as the fenamates, are nonsteroidal antiinflammatory drugs (NSAIDs) that block the metabolism of arachidonic acid by the enzyme cyclooxygenase (CO). Substitution of the carboxylic acid functionality of several fenamates with acidic heterocycles provided dual inhibitors of CO and 5-lipoxygenase (5-LO) activities when tested in an intact rat basophilic leukemia (RBL-1) cell line. Compound 5b (IC50 = 0.77 microM (5-LO), 0.27 microM (CO)) which contains an 1,3,4-oxadiazole-2-thione replacement and 10b (IC50 = 0.87 microM (5-LO), 0.85 microM (CO)) which contains a 1,3,4-thiadiazole-2-thione are the most potent inhibitors of 5-LO and CO activities from these series. Both of these heterocyclic analogs of flufenamic acid are also active in carageenin-induced rat footpad edema (CFE), a model of acute inflammation. When dosed orally the ID50s for 5b and 10b in CFE are 8.5 and 4.7 mg/kg, respectively.
N-芳基邻氨基苯甲酸类，通常称为灭酸类，是一类非甾体抗炎药（NSAIDs），可通过环氧化酶（CO）阻断花生四烯酸的代谢。在完整的大鼠嗜碱性白血病（RBL-1）细胞系中进行测试时，用酸性杂环取代几种灭酸类的羧酸官能团可产生CO和5-脂氧合酶（5-LO）活性的双重抑制剂。含有1,3,4-恶二唑-2-硫酮取代基的化合物5b（IC50 = 0.77 microM（5-LO），0.27 microM（CO））和含有1,3,4-噻二唑-2-硫酮的化合物10b（IC50 = 0.87 microM（5-LO），0.85 microM（CO））是这些系列中5-LO和CO活性最有效的抑制剂。氟芬那酸的这两种杂环类似物在角叉菜胶诱导的大鼠足爪水肿（CFE）（一种急性炎症模型）中也具有活性。口服给药时，5b和10b在CFE中的半数抑制剂量（ID50）分别为8.5和4.7 mg/kg。
