Mitigating Heterocycle Metabolism in Drug Discovery
Mitigating Heterocycle Metabolism in Drug Discovery
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DOI：
10.1021/jm300343m
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发表时间：
2012-07-12
影响因子：
7.3
通讯作者：
Fotsch, Christopher
中科院分区：
文献类型：
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作者：
St Jean, David J., Jr.;Fotsch, Christopher
在过去的几十年里，药物代谢研究在药物设计中发挥着越来越重要的作用。1− 3体外代谢试验4已成为药物发现中化合物常规分析的组成部分。这些分析的数据使药物化学家能够集中精力研究具有改善代谢稳定性的化合物。6详细的代谢物鉴定研究也更经常地进行，这提供了关于如何战略性地替换或阻断代谢不稳定位点的信息。7此外，在药物发现中定期进行体内PK研究，这有助于建立体外-体内PK关系。4 PKDM科学的这些进步对药物发现的积极影响反映在以下事实中：在PKDM相关问题的临床中，更少的候选药物失败。这表明药物化学家正在成功地将PKDM同事产生的数据整合到具有更少代谢负债的化合物的设计中。来自代谢研究的大量数据使药物化学家能够制定减少化合物代谢的一般原则。这些方法包括但不限于降低亲脂性、改变立体和电子学、引入构象约束和改变其化合物的立体化学。虽然没有一种方法能够解决所有的代谢问题，但这些原则确实为药物化学家提供了如何改善其化合物代谢能力的指导。如果已知代谢的特定位点，药物化学家会阻断该位点，通常是用氟，或者用生物电子等排体取代代谢不稳定的基团。9虽然几位作者已经综述了这些降低代谢的技术，5，10，11，但没有综述总结了改善杂环代谢稳定性的不同方法。在这篇综述中，我们总结的例子，在杂环或附近的变化，以提高代谢稳定性。通过总结这些例子，我们希望提供一个有用的指南，药物化学家，因为他们试图改善自己的杂环化合物的代谢概况。大多数的例子，包括在这篇评论来自搜索在线开放存取数据库CHEMBL。12除了从药物化学文献中获得化合物的药理学数据外，CHEMBL还拥有超过120 000个关于化合物ADMET特性的数据点。在可视化软件Spotfire的帮助下，我们能够从CHEMBL ADMET数据中挑选出重点关注杂环的例子。我们还从引用药物代谢领域领先综述的论文中确定了一些例子13 - 18，并在其他最近的药物代谢综述中出现。19 - 22我们对本综述所选例子的主要标准是，为改善代谢而进行的改变必须发生在杂环或其附近。
In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1− 3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro− in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities. Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5, 10, 11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13− 18 and were present in other recent reviews on drug metabolism. 19− 22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle