Drugs that contain strategically placed atoms of deuterium—a heavy isotope of hydrogen—can break down more slowly in the body, potentially making treatments more effective. Now researchers in France have developed a precise and efficient method for swapping specific hydrogen atoms for deuterium, offering medicinal chemists easier access to these “heavy drugs” (Chem Catalysis 2026, DOI: 10.1016/j.checat.2026.101827).
During metabolism, enzymes break carbon-deuterium bonds at a slower rate than the corresponding carbon-hydrogen bonds, a phenomenon called the kinetic isotope effect. This effect can keep a deuterated drug in the body for longer without altering its pharmacology. “That means you can reduce the amount of dosing, or the frequency of dosing, which is a big advantage for patient compliance and ease of prescription,” says David Hesk, director of radiochemistry at RTI International, who has worked on deuterated drugs but was not involved in the new research.
Drugmakers have been interested in exploiting this effect for decades, typically by developing deuterated versions of established drugs. The US Food and Drug Administration approved the first deuterated drug in 2017, and regulators have greenlit a handful of others since then.
For drug developers, though, these molecules can be tricky to make. Resynthesizing a known drug from scratch with deuterated reagents is extremely laborious, so it’s preferable to modify a finished drug molecule by replacing hydrogen with deuterium.
A handful of methods are available currently for making that isotope switch, but most have drawbacks. Some lack selectivity, peppering deuterium onto multiple sites in a molecule. Others do not completely replace hydrogen at the desired location, producing a blend of deuterated and nondeuterated analogs. These mixtures complicate medicinal chemistry studies and regulatory assessments.
“That’s why we needed our new method to be very specific and also to incorporate the maximum deuterium atoms at that position,” explains Sophie Feuillastre of the French Alternative Energies and Atomic Energy Commission (CEA) and Paris-Saclay University, who co-led the study with her colleague Grégory Pieters.
Their approach installs deuterium on carbon atoms adjacent to nitrogen in common heterocycles like pyridines and quinolines. Aldehyde oxidase enzymes oxidize these positions during metabolism, so deuteration is a good way to slow that process.
The method uses deuterium gas (D2) along with a commercially available, air-stable nickel complex that generates catalytic nickel nanoparticles in the reaction. In tests on a dozen known drugs, the method almost completely replaced hydrogen atoms at the desired positions in most of the molecules, without disturbing other functional groups. “It’s very good. I think it’s the first time I’ve seen very specific deuteration at a targeted point,” Hesk says, adding that the method’s convenience should appeal to drug developers.
One of the molecules the researchers tested is famciclovir, a prodrug that is converted in the body to the antiviral agent penciclovir. Deuterating famciclovir tripled the drug’s metabolic half-life to 30 min, and Pieters believes this is the first time deuteration has been used to slow the activation of a prodrug.
The researchers are collaborating with several pharmaceutical companies to apply the method in drug development, and Pieters hopes their approach could eventually be scaled up for manufacturing. “We really need to find some way to decrease the cost of production of these compounds,” he says.
