Novartis Institutes for Biomedical Research, Inc., Metabolism and Pharmacokinetics, Cambridge, MA 02472, USA.
Curr Top Med Chem. 2011;11(4):419-49. doi: 10.2174/156802611794480891.
Metabolic activation of new chemical entities to reactive intermediates is routinely monitored in drug discovery and development. Reactive intermediates may bind to cellular macromolecules such as proteins, DNA and may eventually lead to cell death via necrosis, apoptosis or oxidative stress. The evidence that the ultimate outcome of metabolic activation is an adverse drug reaction manifested as in vivo toxicity, is at best circumstantial. However, understanding the process of bioactivation of structural alerts by trapping the reactive intermediates is critical to guide medicinal chemistry efforts in quest for safer and potent molecules. This commentary provides a brief introduction to adverse drug reactions and mechanisms of reactive intermediate formation for various functional groups, followed by a review of chemical design approaches, examples of such strategies, possible isosteric replacements for structural alerts and rationalization of laboratory approaches to determine reactive intermediates, as a guide to today's medicinal chemist.
在药物发现和开发过程中，通常会监测新化学实体向反应性中间体的代谢激活。反应性中间体可能与细胞大分子（如蛋白质、DNA）结合，并最终通过坏死、凋亡或氧化应激导致细胞死亡。代谢激活的最终结果是表现为体内毒性的不良反应的证据充其量只是间接的。然而，了解结构警示物的生物活化过程，通过捕获反应性中间体来指导药物化学努力，以寻求更安全、更有效的分子，这是至关重要的。本评论简要介绍了各种官能团的不良反应和反应性中间体形成的机制，然后回顾了化学设计方法，此类策略的实例，结构警示物的可能等排体替换以及确定反应性中间体的实验室方法的合理化，以指导当今的药物化学家。
