Alexander J, Cargill R, Michelson S R, Schwam H
INTERx Research Corporation, Merck Sharp and Dohme Research Laboratories, Lawrence, Kansas 66046.
J Med Chem. 1988 Feb;31(2):318-22. doi: 10.1021/jm00397a008.
(Acyloxy)alkyl carbamates of the type R1R2N-CO-O-CHR3-OCO-R4 are described as novel bioreversible prodrugs for primary and secondary amines. These were prepared either by a one-step reaction involving nucleophilic attack on p-nitrophenyl alpha-(acyloxy)alkyl carbonates with displacement of p-nitrophenol or by reaction of alpha-haloalkyl carbamates with silver or mercury salts of carboxylic acids. Enzymatic hydrolysis of the ester bond in these ester carbamates leads to a cascade reaction resulting in rapid regeneration of the parent amine. Permeability measurements of such nonionic derivatives of atenolol, betaxolol, pindolol, propranolol, and timolol through fuzzy rat skin and rabbit cornea mounted on diffusion cells show that derivatization of the hydrophilic beta-blockers results in several-fold increase in permeation through these biological membranes. However, prodrug modification of the lipophilic beta-blockers leads to little advantage in permeability characteristics.
R1R2N-CO-O-CHR3-OCO-R4类型的（酰氧基）烷基氨基甲酸酯被描述为伯胺和仲胺的新型生物可逆前药。这些前药可通过一步反应制备，该反应涉及对对硝基苯基α-（酰氧基）烷基碳酸酯进行亲核攻击并取代对硝基苯酚，或者通过α-卤代烷基氨基甲酸酯与羧酸的银盐或汞盐反应来制备。这些酯氨基甲酸酯中酯键的酶促水解会导致级联反应，从而使母体胺快速再生。通过安装在扩散池上的模糊大鼠皮肤和兔角膜对阿替洛尔、倍他洛尔、吲哚洛尔、普萘洛尔和噻吗洛尔等非离子衍生物的渗透性测量表明，亲水性β受体阻滞剂的衍生化导致通过这些生物膜的渗透增加了几倍。然而，亲脂性β受体阻滞剂的前药修饰在渗透性特征方面几乎没有优势。
