(ACYLOXY)ALKYL CARBAMATES AS NOVEL BIOREVERSIBLE PRODRUGS FOR AMINES - INCREASED PERMEATION THROUGH BIOLOGICAL-MEMBRANES
(ACYLOXY)ALKYL CARBAMATES AS NOVEL BIOREVERSIBLE PRODRUGS FOR AMINES - INCREASED PERMEATION THROUGH BIOLOGICAL-MEMBRANES
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DOI：
10.1021/jm00397a008
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发表时间：
1988-02-01
影响因子：
7.3
通讯作者：
SCHWAM, H
中科院分区：
文献类型：
--
作者：
ALEXANDER, J;CARGILL, R;SCHWAM, H
（酰基）氨基甲酸酯r1r2n .sbd. co .sbd. sbd. chr3 .sbd. oco .sbd。R4被描述为新型生物可逆的伯胺和仲胺前药。这些都是通过亲核攻击对硝基苯的一步反应制备的。-（酰基）羰基碳酸盐与对硝基苯酚置换或反应。-卤代烷基氨基甲酸酯与羧酸的银或汞盐。酶水解这些酯氨基甲酸酯中的酯键导致级联反应，导致母体胺的快速再生。对阿替洛尔、倍他洛尔、品多洛尔、心得洛尔和替马洛尔的非离子衍生物在铺在扩散细胞上的模糊大鼠皮肤和兔角膜上的渗透性测量表明，亲水性的。-阻滞剂导致通过这些生物膜的渗透性增加数倍。然而，药物前修饰的亲脂性。-阻滞剂在渗透特性上几乎没有优势。
(Acyloxy)alkyl carbamates of the type R1R2N.sbd.CO.sbd.O.sbd.CHR3.sbd.OCO.sbd.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 showed 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.