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Sep 13, 2023

Deuterium in drug discovery: progress, opportunities and challenges

Nature Reviews Drug Discovery

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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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This work is part of the project NODES, which has received funding from the MUR-M4C2 1.5 of Piano Nazionale di Ripresa e Resilienza (PNRR) with grant agreement no. ECS00000036.

Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy

Rita Maria Concetta Di Martino & Tracey Pirali

Vertex Pharmaceuticals, Inc., Boston, MA, USA

Brad D. Maxwell

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The authors contributed equally to all aspects of the article.

Correspondence to Tracey Pirali.

T.P. is co-founder and shareholder of the start-up company ChemICare, Italy. B.D.M. is senior scientific fellow in process chemistry at Vertex Pharmaceuticals (Boston, MA, USA) and currently holds shares of stock and options in the company. R.M.C.D.M. declares no competing interests.

Nature Reviews Drug Discovery thanks Volker Derdau and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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ClinicalTrials.gov: https://clinicaltrials.gov

Bioisosteres are structurally distinct compounds bearing atoms or groups that owing to chemical and/or physical similarities elicit broadly similar biological effects.

A term used to describe the development of a single enantiomer of a previously approved racemic drug with the goal of improving on the characteristics of the racemic version.

One of two stereoisomers that cannot be superimposed on each other and are mirror images of each other.

The process of interconversion of one enantiomer into the other.

The process in stereochemistry in which there is a change in the configuration of only one stereocentre in a compound that has more than one stereocentre.

Diastereomers that contain more than one stereocentre and differ from each other in the absolute configuration at only one stereocentre.

Species of the same element that differ in the number of neutrons in the nucleus.

Molecular entities that differ only in isotopic composition (number of isotopic substitutions).

(Also known as isotopic isomers). Isomers having the same number of each isotope, but differing in their positions.

A shift towards a desirable and non-toxic metabolic pathway.

A shift towards a collateral and undesired metabolic pathway.

Sites on molecules that are vulnerable to metabolism by enzymes such as those in the cytochrome P450 family.

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Di Martino, R.M.C., Maxwell, B.D. & Pirali, T. Deuterium in drug discovery: progress, opportunities and challenges. Nat Rev Drug Discov (2023). https://doi.org/10.1038/s41573-023-00703-8

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Accepted: 12 April 2023

Published: 05 June 2023

DOI: https://doi.org/10.1038/s41573-023-00703-8

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