Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.

用重同位素氘取代氢原子需要在分子中添加一个中子。尽管是一个微妙的变化，这种结构修饰（称为氘化）可以改善药物的药代动力学和/或毒性特征，与非氘化对应物相比，有可能转化为功效和安全性的改进。最初，开发这一潜力的努力主要是通过“氘转换”方法开发市售药物的氘代类似物，例如氘代丁苯那嗪，它于 2017 年成为第一个获得 FDA 批准的氘代药物。焦点已转向在新药发现中应用氘化，FDA 于 2022 年批准了开创性的从头氘化药物 deucravacitinib。在这篇综述中，我们重点介绍了氘化在药物发现和开发领域的关键里程碑，强调了最新的、具有指导意义的药物化学计划并讨论药物开发商的机遇和障碍，以及仍有待解决的问题。