In-depth understanding of the structure-based reactive metabolite formation of organic functional groups.

IF 3.4 2区 医学 Q2 PHARMACOLOGY & PHARMACY
Chunyong He, Yuchang Mao, Hong Wan
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引用次数: 0

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a leading cause of drug attrition and/or withdrawal. The formation of reactive metabolites is widely accepted as a key factor contributing to idiosyncratic DILI. Therefore, identifying reactive metabolites has become a critical focus during lead optimization, and a combination of GSH-/cyano-trapping and cytochrome P450 inactivation studies is recommended to identify compounds with the potential to generate reactive metabolites. Daily dose, clinical indication, detoxication pathways, administration route, and treatment duration are the most considerations when deprioritizing candidates that generate reactive metabolites. Removing the structural alerts is considered a pragmatic strategy for mitigating the risk associated with reactive metabolites, although this approach may sometimes exclude otherwise potent molecules. In this context, an in-depth insight into the structure-based reactive metabolite formation of organic functional groups can significantly aid in the rational design of drug candidates with improved safety profiles. The primary goal of this review is to delve into an analysis of the bioactivation mechanisms of organic functional groups and their potential detrimental effects with recent examples to assist medicinal chemists and metabolism scientists in designing safer drug candidates with a higher likelihood of success.

基于结构的有机官能团反应性代谢物形成的深入理解。
特异性药物性肝损伤(DILI)是药物消耗和/或停药的主要原因。反应性代谢物的形成被广泛认为是导致特异性DILI的关键因素。因此,鉴定活性代谢物已成为铅优化过程中的关键焦点,建议结合GSH-/氰捕获和细胞色素P450失活研究来鉴定可能产生活性代谢物的化合物。日剂量、临床适应症、解毒途径、给药途径和治疗时间是优先考虑产生反应性代谢物的候选药物时最需要考虑的因素。消除结构警报被认为是一种实用的策略,可以减轻与反应性代谢物相关的风险,尽管这种方法有时可能会排除其他有效的分子。在这种情况下,深入了解有机官能团的基于结构的反应性代谢物形成可以显着帮助合理设计具有更高安全性的候选药物。本综述的主要目的是深入分析有机官能团的生物活化机制及其潜在的有害影响,并结合最近的例子,以帮助药物化学家和代谢科学家设计更安全、更有可能成功的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Drug Metabolism Reviews
Drug Metabolism Reviews 医学-药学
CiteScore
11.10
自引率
1.70%
发文量
21
审稿时长
1 months
期刊介绍: Drug Metabolism Reviews consistently provides critically needed reviews of an impressive array of drug metabolism research-covering established, new, and potential drugs; environmentally toxic chemicals; absorption; metabolism and excretion; and enzymology of all living species. Additionally, the journal offers new hypotheses of interest to diverse groups of medical professionals including pharmacologists, toxicologists, chemists, microbiologists, pharmacokineticists, immunologists, mass spectroscopists, as well as enzymologists working in xenobiotic biotransformation.
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