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.

氢原子被其重同位素氘取代需要向分子中添加一个中子。尽管是一个微妙的变化，但这种称为氘化的结构修饰可能会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，有可能转化为疗效和安全性的提高。最初，开发这一潜力的努力主要导致通过“氘转换”方法开发上市药物的氘代类似物，例如氘代丁苯那嗪，它于 2017 年成为第一种获得 FDA 批准的氘代药物。在过去的几年里，重点已转移到在新药发现中的应用，FDA 于 2022 年批准了开创性的从头氘代药物 deucravacitinib。在这篇综述中，我们重点介绍了药物发现和开发中氘化领域的关键里程碑，强调了最近具有指导意义的药物化学项目，并讨论了药物开发商的机遇和障碍，以及仍有待解决的问题。