Bolleddula Jayaprakasam, DeMent Kevin, Driscoll James P, Worboys Philip, Brassil Patrick J, Bourdet David L
Department of Drug Metabolism and Pharmacokinetics , Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA, USA.
Drug Metab Rev. 2014 Aug;46(3):379-419. doi: 10.3109/03602532.2014.924962. Epub 2014 Jun 9.
Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and monoamine oxidase (MAOs). The electron rich nitrogen and/or α-carbons are often major sites of metabolism of alicyclic amines. The most common biotransformations include N-oxidation, N-conjugation, oxidative N-dealkylation, ring oxidation, and ring opening. In some instances, the metabolic pathways generate electrophilic reactive intermediates and cause bioactivation. However, potential bioactivation related adverse events can be attenuated by structural modifications. Hence it is important to understand the biotransformation pathways to design stable drug candidates that are devoid of metabolic liabilities early in the discovery stage. The current review provides a comprehensive summary of biotransformation and bioactivation pathways of aliphatic nitrogen containing heterocycles and strategies to mitigate metabolic liabilities.
脂肪族含氮杂环化合物，如哌嗪、哌啶、吡咯烷、吗啉、氮丙啶、氮杂环丁烷和氮杂环庚烷，是药物设计中众所周知的结构单元，也是已批准药物治疗中的重要核心结构。这些核心单元一直是细胞色素P450酶以及其他药物代谢酶（如醛氧化酶和单胺氧化酶）进行代谢攻击的靶点。富电子的氮原子和/或α-碳原子通常是脂环族胺类代谢的主要位点。最常见的生物转化包括N-氧化、N-缀合、氧化性N-脱烷基化、环氧化和开环。在某些情况下，代谢途径会产生亲电反应性中间体并导致生物活化。然而，潜在的与生物活化相关的不良事件可以通过结构修饰来减轻。因此，在发现阶段早期了解生物转化途径以设计没有代谢缺陷的稳定候选药物非常重要。本综述全面总结了脂肪族含氮杂环化合物的生物转化和生物活化途径以及减轻代谢缺陷的策略。
