Manley P W, Allanson N M, Booth R F, Buckle P E, Kuzniar E J, Lad N, Lai S M, Lunt D O, Tuffin D P
J Med Chem. 1987 Sep;30(9):1588-95. doi: 10.1021/jm00392a011.
Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. However, on administration to rabbits the ethyl ester 5d had a short duration of action, due to rapid metabolism and excretion via deesterification and beta-glucuronidation. Attempts at replacing the carboxylate group with other potential pharmacophores were unsuccessful.
制备了4-[[2-(1H-咪唑-1-基)-1-[[(4-甲氧基苯基)甲氧基]甲基]乙氧基]甲基]苯甲酸(5m)的类似物，并将其作为血栓素合酶抑制剂进行评估。5m的一系列酯在完整血小板中亲脂性与TxB2生成抑制之间呈抛物线关系，活性比达唑氧苯高50倍。然而，给兔子给药时，乙酯5d作用持续时间短，这是由于通过脱酯作用和β-葡萄糖醛酸化作用快速代谢和排泄。用其他潜在药效基团取代羧基的尝试未成功。
