The deuterium premium: how deuterating drugs can change pharmaceuticals as we know it

In medicine and the pharmaceutical industry, there is often the problem of finding the right dosage of drugs to properly and efficiently treat medical symptoms. When there is an inefficiency in dosage and effectiveness, it can lead people to self-diagnose and inappropriately increase their dosage, which may cause nasty side effects or even tragically leading to fatal overdose cases.

Thus, it becomes a necessity and a life-saving forgone conclusion that the dosage of medicine we are being recommended to take is truly right for us, and that the amount of drugs in our system is appropriate to perform their job. But in some cases, it is not uncommon for our bodies to metabolize these drugs too quickly, and the premature breakdown of these drugs might be the enabling factor behind our inappropriate increase in dosage.

The breakdown of certain drug compounds by their corresponding metabolic enzymes is achieved by those enzymes stripping the chemical compounds of their hydrogen atoms. So naturally, one can target the exact instance of when the enzyme extracts the hydrogen as the key moment that can help prevent premature breakdown of medical compounds. One way that many researchers and pharmaceutical companies are approaching this problem is through the switch of hydrogen in their compounds for deuterium, hydrogen’s heavier isotope.

This isn’t necessarily a novel concept that is being introduced to the pharmaceutical company. The first major example of a deuterated drug candidate to truly make strides in a clinical setting was the antibiotic fludalanine.

The deuterium in the chemical structure was substituted in for the purpose of blocking the formation of toxic metabolites. However, these same toxic metabolites later showed up in the blood of bronchitis patients, so that’s where that particular chapter ends.

But from the end of that, another chapter begins. In 2014, Dr. Scott L. Harbeson and Dr. Roger D. Tung re-opened the deuterium approach to drug innovation. In their paper, “Deuterium Medicinal Chemistry: A New Approach to Drug Discovery and Development,” they explain the premise of the renewed interest in the deuterium-hydrogen swap in drugs.

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“[Deuteration]  has the unique benefit of retaining the pharmacologic profile of physiologically active compounds while, in certain instances, positively impacting their metabolic fate,” the authors say. “In these favorable cases, deuterium substitution can in principle improve the safety, efficacy, and/or tolerability of a therapeutic agent.”

They sought to find out why there weren’t more deuterated agents for human use and application on the market, considering how “ a greater number of patent filings, the emergence of new companies focused on this area, and the recent entry of several compounds into clinical trials” highlighted a great potential for these new deuterated drugs to hit the market.

Harbeson and Tung explain how the carbon-deuterium C-D bond is heavier and requires more energy to cleave than a C-H bond. Thus this higher activation energy, in theory, would help in offsetting the premature metabolism of drugs with regular C-H bonds. However, it appears that due to mechanism complexities and a “masking” phenomenon involving the ratio of the rates of metabolic reactions between a regular “protonated” compound and its “deuterated” counterpart, there is still an air of unpredictability and challenge.

However, C&EN highlighted the potential of this isotope appeal and the increased safety and effectiveness of both pre-existing and new drugs. In your orgo class, you will likely hear about the importance of enantiomers and chirality, which is akin to the “left-” or “right-handedness” of a given compound. The classic example that many professors, my own included, like to use to underscore the importance of chirality, especially with compounds reacting in the human body, is thalidomide.

Thalidomide, or commercially known as Thalomid or Immunoprin, can exist as two enantiomers: one enantiomer causes the desired effects of alleviating morning sickness in pregnant women. The other enantiomer, unfortunately, can cause serious birth defects, including abnormal (or even missing) limbs, organs, etc. — absolutely horrific for the mother and child, and making it that much more important to pay attention to enantiomers.

Thalidomide-enantiomers

However, it’s also not as easy as simply choosing which enantiomer to administer to the patient and calling it a day: epimerization still happens, meaning that one enantiomer will interconvert to the other, and back again. This is where the potential importance of deuteration comes into play — by swapping deuterium in for hydrogen at the chiral center (where a molecule is distinguished between being left- or right-handed), in theory one can slow down that interconversion between enantiomers and selectively control which enantiomer they administer. In fact, this is exactly the project (amongst others) that DeuteRx are working on: using a deuterated thalidomide analog to act as an anticancer agent.

This may be all good and well, but you may be wondering how exactly is deuterium more relevant to your life in the immediate future? Where does it come from and how is it useful outside of the pharmaceutical industry?

Deuterium is found in naturally occurring deuterated “heavy” water, or 0.0155% of the hydrogen nuclei in Earth’s ocean waters. It can be extracted from different methods, one common method being the Girdler sulfide process (I’ll let someone else explain that process more thoroughly). Any chemist will tell you exactly how valuable deuterium is to their research. Though it may be a bit early, you will certainly be tested in your orgo courses on NMR spectra and how they work (which one can master with our “NMR Center”!). In NMR, it is important to use deuterated solvents. Being based on magnetic resonance, modern NMR spectrometers use the concentration of deuterium in solvents to stabilize the magnetic field strength and take accurate readings. Furthermore, since there is a lot more solvent in an NMR sample than there is compound that one is trying to study (usually to distinguish how many unique proton environments there are), it makes sense why deuterium is so important to lower the signal-to-noise ratio and obtain a “clean” reading.

The usefulness of deuterium has been so important and widely known by chemists for so long, and their application towards pharmaceuticals has renewed interest — and for good reason. Their incorporation into existing and new medicine could lead to increased effectiveness at lower dosages, thus improving so many people’s lives.

Miko