A deuterated drug is a small molecule medicinal product in which one or more of the hydrogen atoms in the drug molecule have been replaced by its heavier stable isotope deuterium. Because of the kinetic isotope effect, deuterium-containing drugs may have significantly lower rates of metabolism, and hence a longer half-life. [1] [2] [3]
Hydrogen is a chemical element with an atomic number of 1. It has one proton and one electron. Deuterium is the heavier naturally-occurring stable isotope of hydrogen. Deuterium was discovered by Harold Urey in 1931, for which he received the Nobel Prize in 1934. The deuterium isotope effect has become an important tool in the elucidation of the mechanism of chemical reactions. Deuterium contains one proton, one electron, and a neutron, effectively doubling the mass of the deuterium isotope without changing its properties significantly. However, the C–D bond is a bit shorter, [4] and it has reduced electronic polarizability and less hyperconjugative stabilization of adjacent bonds, including developing an anti-bonding orbital as part of the newly formed bond. This can potentially result in weaker van der Waals stabilization, and can produce other changes in properties that are difficult to predict, including changes in the intramolecular volume and the transition state volume. [3] Substituting deuterium for hydrogen yields deuterated compounds that are similar in size and shape to hydrogen-based compounds.
The concept of replacing hydrogen with deuterium is an example of bioisosterism, whereby similar biological effects to a known drug are produced in an analog designed to confer superior properties. [5] The first patent in the US granted for deuterated molecules was in the 1970s. Since then patents on deuterated drugs have become more common. [6]
The applications of the deuterium isotope effect has increased over time, and it is now applied extensively in mechanistic studies of the metabolism of drugs as well as other studies focused on pharmacokinetics (PK), efficacy, tolerability, bioavailability, and safety. [7] The introduction of deuterated drug candidates that began in the 1970s evolved from earlier work with deuterated metabolites. However, it took more than 40 years for the first deuterated drug, Austedo® (deutetrabenazine), to be approved by the FDA. [8] Numerous publications have discussed the advantages and disadvantages of deuterated drugs. [8] [9] [1] [2] [3] A number of publications have discussed aspects of intellectual property of deuterated versions of drugs. [10] [11] [12]
Deutetrabenazine is a deuterated version of tetrabenazine. It was developed by Auspex then acquired by Teva in 2015 [13] and approved by the FDA in 2017 as a treatment for chorea associated with Huntington's disease; it has a longer half life than the non-deuterated form of tetrabenazine, which had been approved earlier for the same use. [14]
Deucravacitinib is a deuterated [15] JAK inhibitor (specifically, TYK2 inhibitor) [16] approved for the treatment of plaque psoriasis. [17]
Concert Pharmaceuticals focuses on deuterated drugs for various conditions. [18] [19] [20] Concert was acquired by Sun Pharma in March 2023. [21]
The company Retrotope discovered and has been developing a deuterated fatty acid RT001 as a treatment for neurodegenerative diseases such as Friedreich's ataxia and infantile neuroaxonal dystrophy. Their premise is that fatty acids in cell membranes are a source of reactive oxygen species and deuterated versions will be less prone to generating them. [22] [23]
Poxel SA, a French clinical-stage biopharmaceutical company focused on therapies for rare metabolic diseases, is developing PXL065 to target nonalcoholic steatohepatitis (NASH). The company acquired PXL065 (the deuterium-stabilized (R)-enantiomer of pioglitazone) and a portfolio of deuterated thiazolidinediones (TZDs) from DeuteRx, LLC, in 2018, [24] and published positive results from the Phase 2 trial in March 2023. [25]
| Compound | Status | Beneficial deuterium effect |
|---|---|---|
| Fludalanine (MK-0641) | Discontinued | Reduce toxic metabolite, 3-fluorolactate |
| Austedo (deutetrabenazine) (SD-809) | Approved | Reduce formation of toxic metabolite by CYP2D6 |
| ALK-001 (d3-vitamin A) | Phase 3 | Slows the dimerization rate of vitamin A |
| AVP-786 (d6-dextromethorphan) | Phase 3 | Reduce formation of toxic metabolite by CYP2D6 |
| VX-561 (formerly CTP-656) (d9-ivacaftor) | Phase 2 | Reduce rate of tert-Bu group oxidation and in vivo clearance by CYP3A4 |
| VX-984 (Novel cancer agent) | Phase 1 | Reduce aldehyde oxidase-driven metabolism |
| PXL065 (formerly DRX-065 [24] ) (d1-(R)-pioglitazone) [26] | Phase 2 | Stabilize preferred R-enantiomer to obtain mitochondrial function modulation without peroxisome proliferator-activated receptor gamma (PPARγ) agonist activity (due to S-pioglitazone) [27] [25] |
| RT001 (d2-linoleic acid ethyl ester) | Phase 1/2 | Limit lipid peroxidation |
| SP-3164 (formerly DRX-164 [28] ) (d-(S)-avadomide) | Preclinical | Stabilize preferred S-enantiomer for increased cereblon (CRBN) binding affinity [29] |
Deuterium (hydrogen-2, symbol 2H or D, also known as heavy hydrogen) is one of two stable isotopes of hydrogen (the other is protium, or hydrogen-1). The deuterium nucleus, called a deuteron, contains one proton and one neutron, whereas the far more common protium has no neutrons in the nucleus. Deuterium has a natural abundance in Earth's oceans of about one atom of deuterium among every 6,420 atoms of hydrogen (see heavy water). Thus deuterium accounts for about 0.0156% by number (0.0312% by mass) of all hydrogen in the oceans: 4.85×1013 tonnes of deuterium – mainly in form of HOD (or 1HO2H or 1H2HO) and only rarely in form of D2O (or 2H2O) – in 1.4×1018 tonnes of water. The abundance of deuterium changes slightly from one kind of natural water to another (see Vienna Standard Mean Ocean Water).
Heavy water is a form of water whose hydrogen atoms are all deuterium rather than the common hydrogen-1 isotope that makes up most of the hydrogen in normal water. The presence of the heavier isotope gives the water different nuclear properties, and the increase in mass gives it slightly different physical and chemical properties when compared to normal water.
The Girdler sulfide (GS) process, also known as the Geib–Spevack (GS) process, is an industrial production method for filtering out of natural water the heavy water (deuterium oxide = D2O) which is used in particle research, in deuterium NMR spectroscopy, deuterated solvents for proton NMR spectroscopy, in heavy water nuclear reactors (as a coolant and moderator) and in deuterated drugs.
Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s.
In chemistry, isotopologues are molecules that differ only in their isotopic composition. They have the same chemical formula and bonding arrangement of atoms, but at least one atom has a different number of neutrons than the parent.
Hydrogen–deuterium exchange is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom, or vice versa. It can be applied most easily to exchangeable protons and deuterons, where such a transformation occurs in the presence of a suitable deuterium source, without any catalyst. The use of acid, base or metal catalysts, coupled with conditions of increased temperature and pressure, can facilitate the exchange of non-exchangeable hydrogen atoms, so long as the substrate is robust to the conditions and reagents employed. This often results in perdeuteration: hydrogen-deuterium exchange of all non-exchangeable hydrogen atoms in a molecule.
Deuterated chloroform, also known as chloroform-d, is the organic compound with the formula CDCl3. Deuterated chloroform is a common solvent used in NMR spectroscopy. The properties of CDCl3 and ordinary CHCl3 (chloroform) are virtually identical.
Deuterated acetone ((CD3)2CO), also known as acetone-d6, is a form (isotopologue) of acetone (CH3)2CO in which the hydrogen atom (H) is replaced with deuterium (heavy hydrogen) isotope (2H or D). Deuterated acetone is a common solvent used in NMR spectroscopy.
Deuterated benzene (C6D6) is an isotopologue of benzene (C6H6) in which the hydrogen atom ("H") is replaced with deuterium (heavy hydrogen) isotope ("D").
Heavy isotope diet is the consumption of nutrients in which some atoms are replaced with their heavier non-radioactive isotopes, such as deuterium(2H) or heavy carbon (13C). Biomolecules that incorporate heavier isotopes give rise to more stable molecular structures under certain circumstances, which is hypothesized to increase resistance to damage associated with ageing or diseases.
Alogliptin, sold under the brand names Nesina and Vipidia, is an oral anti-diabetic drug in the DPP-4 inhibitor (gliptin) class. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of hypoglycemia, and has relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in people whose diabetes cannot adequately be controlled with metformin alone.
Deuterium-depleted water (DDW) is water which has a lower concentration of deuterium than occurs naturally at sea level on Earth.
This is a list of women chemists. It should include those who have been important to the development or practice of chemistry. Their research or application has made significant contributions in the area of basic or applied chemistry.
Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor which is used for the treatment of chorea associated with Huntington's disease and tardive dyskinesia.
Deulinoleate ethyl is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), a part of reinforced lipids. It is an isotopologue of linoleic acid, an essential omega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.
Retrotope, Inc. is a drug development company advancing the idea that polyunsaturated fatty acids (PUFA) drugs fortified with heavy isotopes protect living cells by making bonds within the delicate molecules inside and around cells harder to break. This makes the cells less prone to damage caused by reactive oxygen species (ROS), one of the principal causes of ageing and age-associated diseases. Founded in 2006 by entrepreneurs and scientists with seed funding from private investors, Retrotope is developing a non-antioxidant approach to preventing lipid peroxidation, a detrimental factor in mitochondrial, neuronal, and retinal diseases. The company employs the virtual business model and works in scientific collaboration with more than 80 research groups in universities worldwide.
Kinetic isotope effect is observed when molecules containing heavier isotopes of the same elements engage in a chemical reaction at a slower rate. Deuterium-reinforced lipids can be used for protecting living cells by slowing the chain reaction of lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, drugs that stop the chain reaction of lipid peroxidation have preventive and therapeutic potential.
Reinforced lipids are lipid molecules in which some of the fatty acids contain deuterium. They can be used for the protection of living cells by slowing the chain reaction due to isotope effect on lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, use of reinforced lipids that stop the chain reaction of lipid peroxidation has preventive and therapeutic potential.
Deucravacitinib, sold under the brand name Sotyktu, is a medication used for the treatment of moderate-to-severe plaque psoriasis. It is a tyrosine kinase 2 (TYK2) inhibitor and it is taken by mouth. It was developed by Bristol Myers Squibb.
PXL065 (d-R-pioglitazone) is a drug candidate for the treatment of nonalcoholic steatohepatitis (NASH). It is the deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonist activity and the associated side effects of weight gain and edema. PXL065 (formerly known as DRX-065) has demonstrated preclinical efficacy for both NASH and X-linked adrenoleukodystrophy (X-ALD). In 2022, it successfully completed a 9 month Phase 2 trial in biopsy-proven NASH patients where it met the primary endpoint for reduction in liver fat without weight gain or edema.