Unangst P C, Shrum G P, Connor D T, Dyer R D, Schrier D J
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
J Med Chem. 1992 Oct 2;35(20):3691-8. doi: 10.1021/jm00098a015.
A series of 1,2,4-oxadiazoles and 1,2,4-thiadiazoles containing a 2,6-di-tert-butylphenol substituent were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. Several of these compounds show oral efficacy in the rat carrageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models, without concomitant gastric ulceration. Structure-activity relationships are discussed. The best compounds (ID40 values in MFE of 3-8 mg/kg po) contain guanidine-derived substituents on the heterocyclic ring.
制备了一系列含有2,6 -二叔丁基苯酚取代基的1,2,4 -恶二唑和1,2,4 -噻二唑，并在大鼠嗜碱性白血病（RBL - 1）细胞中作为5 -脂氧合酶和环氧化酶的双重抑制剂进行了评估。其中几种化合物在大鼠角叉菜胶足垫水肿（CFE）和分枝杆菌足垫水肿（MFE）抗炎模型中显示出口服疗效，且无伴随的胃溃疡。讨论了构效关系。最佳化合物（在MFE中的口服半数有效剂量值为3 - 8 mg/kg）在杂环上含有胍衍生的取代基。
