Designing around Structural Alerts in Drug Discovery
Designing around Structural Alerts in Drug Discovery
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DOI：
10.1021/acs.jmedchem.9b00917
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发表时间：
2020-06-25
影响因子：
7.3
通讯作者：
Kalgutkar, Amit S.
中科院分区：
文献类型：
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作者：
Kalgutkar, Amit S.
几十年来的累积研究表明，反应性代谢物参与了许多特异性药物不良反应（IADRs）。因此，“避免”策略已被插入到药物发现范例中，其中包括排除结构警报和可能终止反应性代谢物阳性化合物。本文介绍了几个值得注意的例子，其中反应性代谢物相关的负债已通过结构代谢研究得到解决。在解决回避策略的局限性和进一步完善药物开发中管理反应性代谢物问题的过程方面也取得了相当大的进展。这些努力主要源于观察到许多含有结构警报和/或形成反应性代谢物的药物没有不良反应。展望还深入分析了结构警报/反应性代谢物概念，并讨论了支持反应性代谢物阳性候选药物进展的风险缓解策略。
Cumulative research over several decades has implicated the involvement of reactive metabolites in many idiosyncratic adverse drug reactions (IADRs). Consequently, "avoidance" strategies have been inserted into drug discovery paradigms, which include the exclusion of structural alerts and possible termination of reactive metabolite-positive compounds. Several noteworthy examples where reactive metabolite-related liabilities have been resolved through structure-metabolism studies are presented herein. Considerable progress has also been made in addressing the limitations of the avoidance strategy and further refining the process of managing reactive metabolite issues in drug development. These efforts primarily stemmed from the observation that numerous drugs, which contain structural alerts and/or form reactive metabolites, are devoid of ADRs. The Perspective also dwells into an analysis of the structural alert/ reactive metabolite concept with a discussion of risk mitigation tactics to support the progression of reactive metabolite-positive drug candidates.