Deuterium in drug discovery: progress, opportunities and challenges

by Selleckchem | Sep 05 2023

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.

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Deuteration, the process of replacing a hydrogen atom with its heavy isotope deuterium, has gained significant attention in the field of drug discovery and development. This structural modification offers the potential to improve the pharmacokinetic and toxicity profiles of drugs, leading to enhanced efficacy and safety compared to their non-deuterated counterparts.

Initially, researchers focused on developing deuterated analogues of existing drugs using a "deuterium switch" approach. One notable example is deutetrabenazine, which was the first deuterated drug to receive approval from the U.S. Food and Drug Administration (FDA) in 2017. By incorporating deuterium into the molecular structure, deutetrabenazine exhibited improved pharmacokinetic properties, resulting in a longer half-life and reduced metabolic clearance.

In recent years, there has been a shift towards applying deuteration in the discovery of novel drugs. This approach involves incorporating deuterium early in the drug development process rather than as a modification of existing drugs. An example of this is the FDA's approval of deucravacitinib in 2022, which became the first de novo deuterated drug. Deucravacitinib is an oral therapy for multiple sclerosis, and the inclusion of deuterium in its structure enhances its metabolic stability and decreases potential drug-drug interactions.

Several medicinal chemistry programs have contributed to the advancements in deuteration. These programs have explored the effects of deuteration on various aspects of drug properties, including metabolic stability, protein binding, solubility, and distribution. By strategically incorporating deuterium atoms, medicinal chemists can fine-tune these properties to optimize drug efficacy and safety.

Despite the progress in the field, there are still challenges and questions that need to be addressed. The precise mechanisms by which deuteration affects drug properties are not fully understood, and further research is required to elucidate these effects. Additionally, the synthesis and manufacturing of deuterated drugs present unique challenges due to the increased cost and complexity associated with working with deuterium.

In conclusion, the field of deuteration in drug discovery and development has witnessed significant milestones, from the development of deuterated analogues of existing drugs to the approval of de novo deuterated drugs. The application of deuteration offers promising opportunities for improving drug efficacy and safety. However, further research, collaboration, and technological advancements are needed to fully harness the potential of deuteration in the pharmaceutical industry.