Saari W S, Schwering J E, Lyle P A, Smith S J, Engelhardt E L
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
J Med Chem. 1990 Jan;33(1):97-101. doi: 10.1021/jm00163a016.
A series of basic carbamates of 4-hydroxyanisole was prepared and evaluated as progenitors of this melanocytotoxic phenol. All of the carbamates were relatively stable at low pH but released 4-hydroxyanisole cleanly at pH 7.4 at rates that were structure dependent. A detailed study of the N-methyl-N-[2-(methylamino)ethyl]carbamate showed that generation of the parent phenol followed first-order kinetics with t1/2 = 36.3 min at pH 7.4, 37 degrees C, and was accompanied by formation of N,N'-dimethylimidazolidinone. These basic carbamates are examples of cyclization-activated prodrugs in which generation of the active drug is not linked to enzymatic cleavage but rather depends solely upon a predictable, intramolecular cyclization-elimination reaction.
制备了一系列4-羟基苯甲醚的碱性氨基甲酸酯，并将其作为这种黑素细胞毒性酚的前体进行评估。所有氨基甲酸酯在低pH值下相对稳定，但在pH 7.4时能以与结构相关的速率干净地释放出4-羟基苯甲醚。对N-甲基-N-[2-(甲氨基)乙基]氨基甲酸酯的详细研究表明，母体酚的生成遵循一级动力学，在pH 7.4、37℃时t1/2 = 36.3分钟，同时伴有N,N'-二甲基咪唑啉酮的形成。这些碱性氨基甲酸酯是环化激活前药的例子，其中活性药物的生成与酶促裂解无关，而是仅取决于可预测的分子内环化消除反应。
