期刊
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 51, 2011
卷 51, 期 -, 页码 145-167出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010510-100514
关键词
structural alerts; electrophiles; radicals; fluorination; oxidative stress
Bioactivation through drug metabolism is frequently suspected as an initiating event in many drug toxicities. The CYP450 and peroxidase enzyme systems are generally considered the most important groups of enzymes involved in bioactivation, producing either electrophilic or radical metabolites. Drug design efforts routinely consider these factors, and a number of structural alerts for bioactivation have been identified. Among the most frequently encountered structural alerts are aromatic systems with electron-donating substituents and some five-membered heterocycles. Metabolism of these groups can lead to chemically reactive electrophiles. Strategies that have been used to minimize the associated risk involve replacing the structural-alert moiety, blocking or making metabolism less favorable, and incorporating metabolic soft spots to facilitate metabolism away from the structural-alert substituent. The metabolism of drugs to radicals usually leads to cellular oxidative stress. The formation of radical metabolites can be minimized through the use of similar approaches but remains an area less frequently considered in drug design.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据