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Deuterated CompoundsPosted on 2018-07-14 12:19:58

Deuterated Compounds:

Deuterium - D or 2H also known as heavy hydrogen is one of two stable isotopes of hydrogen. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made to a molecule.

Hydrogen consists of one electron and one proton and has an atomic mass of approximately 1.0 atomic mass unit (AMU). Deuterium also has a single electron but its nucleus contains one neutron and one proton, resulting in an atomic mass of approximately 2.0 AMU. Deuterium occurs at a natural abundance of approximately 0.0015%, which allows it to be sourced from bulk water to produce highly enriched D2O (heavy water). D2O is available on a large scale due to the need for multi ton quantities of heavy water used in nuclear reactors. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be exchanged directly into finished drug compounds or into reagents that are useful for synthesizing drug molecules. Deuterium gas is also a useful starting material for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic bonds is a rapid route for incorporation of deuterium.

The first deuterated drug has been approved by the FDA. It’s Austedo (Deutetrabenazine), from Teva, and it targets Huntington’s chorea. This is an interesting development on several levels. The idea of adding deuterium (instead of plain hydrogen) to drug structures had been kicking around for many years.

Pros of deuterium:

Selective replacement of hydrogen atoms with deuterium (deuteration) has the unique benefit of retaining the pharmacologic profile of physiologically active compounds while, in certain instances, positively impacting their metabolic fate.

In some favourable cases, deuterium substitution can in principle improve the safety, efficacy, and/or tolerability of a therapeutic agent.

Selective deuteration of compounds such as approved drugs with well-defined human pharmacological effects can potentially provide an efficient and accelerated approach to creating significantly differentiated, patentable new medicines that address important unmet medical needs.

Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium-carbon bond modifying their metabolism.

Drugs that contain deuterium may have significantly lower metabolism rates. As the C-D bond is ten times stronger than the C-H bond, it is much more resistant to chemical or enzymatic cleavage and the difficulty of breaking the bond can decrease the rate of metabolism. Lower metabolism rates give deuterated drugs a longer half-life, making them take much longer to be eliminated from the body. This reduced metabolism can extend a drug’s desired effects, diminish its undesirable effects, and allow less frequent dosing. The replacement may also lower toxicity by reducing toxic metabolite formation.

Predominantly pre-systemic effect of deuteration, which we have observed in a number of instances. In such cases, reduced rates of (usually oxidative) metabolism in the gut wall and/or liver result in a larger percentage of not metabolised drug reaching systemic circulation. In many cases, the rate of systemic clearance is unchanged. Deuterated drugs showing this effect may have reduced dosing requirements and produce lower metabolite loads. Since gastrointestinal irritation has been related to the amount of dosed compound rather than blood concentration for certain drugs, this effect could allow enhanced tolerability and/or the ability to achieve a higher maximum tolerated dose.

A major potential advantage of deuterated compounds is the possibility of faster, more efficient, less costly clinical trials, because of the extensive testing the non-deuterated versions have previously undergone. The main reasons compounds fail during clinical trials are lack of efficacy, poor

pharmacokinetics or toxicity. With deuterated drugs, efficacy is not in question – allowing the research to focus on pharmacokinetics and toxicity.

Advantages of deuterated compounds over non-deuterated therapeutic compounds—known as the “Deuterium Switch.”

1. Avoid many of the costs of preclinical development as much has already been done

2. Benefit from significant bodies of clinical knowledge upon the non-deuterated compound to guide clinical development and lower clinical costs

3. Benefit from new patent protections upon these deuterated compounds

4. Lead to improved therapies and patient outcomes. Not surprisingly, there has been a lot of interest in this business model, and most large pharmaceutical companies

Growing Opportunity for Deuterated Drugs

Deuterium modification provides a novel opportunity to develop new drugs by building upon existing scientific or clinical experience, potentially significantly reducing time, risk, and expense. Deuterium is a safe, non-radioactive, naturally abundant isotope of hydrogen. The body of the average human adult already contains about 2 g of deuterium. Due to its similarity to hydrogen, deuterium modification usually has negligible effect on the intrinsic activity of a drug at its biological target. As many drugs under development or on the market suffer from sub-optimal pharmacokinetic and metabolic profiles, deuterium modification offers great promise to improve the profiles of these drugs and open opportunities for new uses. Advance number of deuterium-containing novel compounds designed to have unique therapeutic properties. The company has made preclinical and clinical progress with proprietary drug compounds in diverse therapeutic areas, including potential treatments for diabetic nephropathy, hot flashes, spasticity, neuropathic pain and multiple myeloma.

Deuterium modification may be used broadly to improve upon previously known compounds or their analogs, in turn offering potential benefits in a wide range of therapeutic areas.

Deuterium medicinal chemistry offers a subtle, but at times powerful tool that is only recently achieving widespread attention in the context of new therapeutic agents. Selective deuteration retains biochemical potency and selectivity, but can sometimes enable substantial benefits to the overall pharmacological profile of the resulting compounds. When applied to compounds with well understood therapeutic utility, selective deuteration can be a unique risk-reduced approach to creating new chemical entity drugs that address significant unmet medical needs. More deuterium-containing compounds entering clinical evaluation, it appears increasingly likely that the approach will succeed in producing important new medicines.

The early clinical evaluation of several candidate compounds has been encouraging, supporting the potential for important new deuterated drugs to reach the market.

The advancement of these compounds in clinical trials is highly promising. Compounds are being tested that address patient needs in important disease states, such as Huntington disease and there is a good deal of excitement in the field. Since much of the groundwork for these trials has been performed upon the non-deuterated versions, there is great hope that this will enable faster, smarter and cheaper trials of the deuterated version.