Metabolism and Bioactivation: It's Time to Expect the Unexpected.,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Metabolism and Bioactivation: It's Time to Expect the Unexpected.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-08 , DOI: 10.1021/acs.jmedchem.0c00026
James P Driscoll ₁ , Corinne M Sadlowski ₁ , Nina R Shah ₁ , Antonio Feula ₁

Affiliation

Improvements in in vitro ADME tools and pharmacokinetic prediction models have helped to shift attrition rates in early clinical trials from poor exposure to drug safety concerns, such as drug-induced liver injury (DILI). Assessing a new chemical entity’s potential for liver toxicity is an important consideration for the likely success of new drug candidates. Reactive intermediates produced during drug metabolism have been implicated as a cause of DILI, and their formation has been correlated to the addition of a black box warning on a drug label. In this work, we will present contemporary examples of the bioactivation of atypical structures usually regarded as benign and often used by medicinal chemists when attempting to avoid bioactivation. Medicinal chemistry strategies used to derisk bioactivation will be discussed, and an emphasis will be placed on the necessity of a multidisciplinary approach.

中文翻译：

代谢和生物激活：现在是时候期待意外的事情了。

体外改善ADME工具和药代动力学预测模型已帮助将早期临床试验中的流失率从对药物安全性问题的不良接触（例如，药物诱发的肝损伤（DILI））暴露程度降低。评估新化学实体的肝毒性潜力是新药候选药物可能成功的重要考虑因素。药物代谢过程中产生的反应性中间体被认为是DILI的原因，其形成与药物标签上黑匣子警告的添加有关。在这项工作中，我们将提供非典型结构生物活化的当代实例，这些非生物结构通常被认为是良性的，并且在尝试避免生物活化时经常被药物化学家使用。将讨论用于消除生物活化作用的药物化学策略，

更新日期：2020-04-08

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11