Amsberry K L, Borchardt R T
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
Pharm Res. 1991 Mar;8(3):323-30. doi: 10.1023/a:1015885213625.
Several amides of 3-(3',6'-dioxo-2',4'-dimethylcyclohexa-1',4'-diene)-3,3- dimethylpropionic acid (2) have been synthesized and tested as model redox-sensitive pro-prodrugs of amines. The reduction of these model pro-prodrugs generated hydroxy amide intermediates 4a-4h, the lactonization of which resulted in amine release. The rates of lactonization of 4a-4h were investigated at pH 7.4 and 37 degrees C. The half-lives for appearance of the product lactone 1a from these intermediates were found to range from 1.4 to 3.4 min. With such rapid lactonization rates, it is believed that reduction will be the rate-limiting step in the two-step conversion of the pro-prodrug to the amine.
已合成了几种3-(3',6'-二氧代-2',4'-二甲基环己-1',4'-二烯)-3,3-二甲基丙酸(2)的酰胺，并作为胺类的模型氧化还原敏感前药进行了测试。这些模型前药的还原产生了羟基酰胺中间体4a-4h，其内酯化导致胺的释放。在pH 7.4和37℃下研究了4a-4h的内酯化速率。发现这些中间体生成产物内酯1a的半衰期为1.4至3.4分钟。由于内酯化速率如此之快，据信还原将是前药两步转化为胺的限速步骤。
