Deuterated drug

Short description: Class of pharmaceutical drug

Chemical structures of ethyl linoleate — natural (top) and its deuterated version 11,11-D2-ethyl linoleate. Protium hydrogen atoms (H) are explicitly shown where they are replaced with deuterium atoms (D).

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drug is a small molecule medicinal product in which one or more of the hydrogen atoms in the drug molecule have been replaced by the heavier stable isotope deuterium.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, than their non-deuterated isotopologs.[1][2][3]

## Contents

* 1 Mode of action
* 2 History
* 3 Examples
* 4 See also
* 5 References
* 6 Further reading

## Mode of action

Hydrogen is a chemical element with an atomic number of 1. Its most common isotope, sometimes called "protium", has one proton and one electron. Deuterium, often indicated by the symbol D, 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 additionally one neutron, effectively doubling the mass of the hydrogen atom without changing its properties significantly. However, the carbon–deuterium (C–D) bond is slightly 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 molecular 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.

## History

The concept of replacing protium 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 granted in the US for deuterated molecules was in the 1970s. Since then, patents on deuterated drugs have become more common.[6] Biochemist and inventor Anthony Czarnik holds multiple patents for using deuterium substitution in drug discovery.[7]

The applications of the deuterium isotope effect have increased over time, and it is now applied extensively in mechanistic studies of the metabolism of drugs as well as in other studies focused on pharmacokinetics (PK), efficacy, tolerability, bioavailability, and safety.[8] 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 in the US.[9] Czarnik has invented drugs such as (R)-d1-lenalidomide and (R)-d1-pioglitazone for clinical studies.[10][11]

Numerous publications have discussed the advantages and disadvantages of deuterated drugs.[9][12][1][2][3] A number of publications have discussed aspects of intellectual property of deuterated versions of drugs.[13][14][15]

## Examples

Deutetrabenazine is a deuterated version of tetrabenazine. It was developed by Auspex, then acquired by Teva in 2015[16] 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.[17]

Deucravacitinib is a deuterated[18] JAK inhibitor (specifically, TYK2 inhibitor)[19] approved for the treatment of plaque psoriasis.[20]

Concert Pharmaceuticals focuses on deuterated drugs for various conditions.[21][22][23] Concert was acquired by Sun Pharma in March 2023.[24]

Deutivacaftor is a deuterated version of ivacaftor, developed by Concert and acquired by Vertex Pharmaceuticals, which originally devoped and marketed ivacaftor for the treatment of cystic fibrosis.[25] Deutivacaftor is approved for the same indication, in combination with tezacaftor and vanzacaftor.[26]

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.[27][28]

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,[29] and published positive results from the Phase 2 trial in March 2023.[30]

Compound  | Status  | Beneficial deuterium effect

|
|

Austedo (deutetrabenazine) (SD-809)  | Approved  | Reduces formation of toxic metabolite by CYP2D6
Deutivacaftor (formerly CTP-656, VX-561) (d9-ivacaftor)  | Approved  | Reduces rate of tert-Bu group oxidation and in vivo clearance by CYP3A4
ALK-001 (d3-vitamin A)  | Phase 3  | Slows the dimerization rate of vitamin A
AVP-786 (d6-dextromethorphan)  | Phase 3  | Reduces formation of toxic metabolite by CYP2D6
VX-984 (novel cancer agent)  | Phase 1  | Reduces aldehyde oxidase-driven metabolism
PXL065 (formerly DRX-065[29]) (d1-(R)-pioglitazone)[31] | Phase 2  | Stabilizes preferred R-enantiomer to obtain mitochondrial function modulation without peroxisome proliferator-activated receptor gamma (PPARγ) agonist activity (due to S-pioglitazone)[32][30]
RT001 (d2-linoleic acid ethyl ester)  | Phase 1/2  | Limits lipid peroxidation
SP-3164 (formerly DRX-164[33]) (d-(S)-avadomide)  | Preclinical  | Stabilizes preferred S-enantiomer for increased cereblon (CRBN) binding affinity[34]
Fludalanine (MK-0641)  | Discontinued  | Reduces toxic metabolite, 3-fluorolactate

## See also

* Reinforced lipids

## References

1. ↑ 1.0 1.1 "Big interest in heavy drugs". Nature 458 (7236): 269. March 2009. doi:10.1038/458269a. PMID 19295573.
2. ↑ 2.0 2.1 "Heavy drugs draw heavy interest from pharma backers". Nature Medicine 19 (6): 656. June 2013. doi:10.1038/nm0613-656. PMID 23744136.
3. ↑ 3.0 3.1 3.2 "Using deuterium in drug discovery: leaving the label in the drug". Journal of Medicinal Chemistry 57 (9): 3595–3611. May 2014. doi:10.1021/jm4007998. PMID 24294889.
4. ↑ "Electron-Diffraction Study of the Structures of C2H4 and C2D4". The Journal of Chemical Physics 42 (8): 2683–6. April 1965. doi:10.1063/1.1703223. Bibcode: 1965JChPh..42.2683B.
5. ↑ "Synopsis of some recent tactical application of bioisosteres in drug design". Journal of Medicinal Chemistry 54 (8): 2529–2591. April 2011. doi:10.1021/jm1013693. PMID 21413808.
6. ↑ "Drugs that live long will prosper". The Economist. ISSN 0013-0613. https://www.economist.com/news/science-and-technology/21663193-simple-change-some-pharmaceuticals-might-boost-their-efficacy-and-make-few.
7. ↑ "Google Patents Database". https://patents.google.com/?inventor=Anthony+W+Czarnik.
8. ↑ "Applications of Deuterium in Medicinal Chemistry". Journal of Medicinal Chemistry 62 (11): 5276–5297. June 2019. doi:10.1021/acs.jmedchem.8b01808. PMID 30640460.
9. ↑ 9.0 9.1 "A Decade of Deuteration in Medicinal Chemistry". Platform Technologies in Drug Discovery and Validation. Annual Reports in Medicinal Chemistry. 50. 2017. pp. 519–542. doi:10.1016/bs.armc.2017.08.010. ISBN 978-0-12-813069-8.
10. ↑ Czarnik, Anthony W. (3 September 2013). "Deuterium-enriched bupropion". https://patents.google.com/patent/US8524780B2/en.
11. ↑ Czarnik, Anthony W. (25 July 2017). "Deuterium-enriched aldehydesDeuterium-enriched aldehydes". https://patents.google.com/patent/US9713330B1/en?oq=US9713330B1.
12. ↑ "Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design". Advances in Drug Research 14: 1–40. 1985.
13. ↑ "Deuterated drugs; updates and obviousness analysis". Expert Opinion on Therapeutic Patents 27 (12): 1353–1361. December 2017. doi:10.1080/13543776.2017.1378350. PMID 28885861.
14. ↑ "Deuterated drugs: where are we now?". Expert Opinion on Therapeutic Patents 24 (10): 1067–1075. October 2014. doi:10.1517/13543776.2014.943184. PMID 25069517.
15. ↑ "Deuterated Drugs: Unexpectedly Nonobvious?". Journal of High Technology Law 10 (1): 22–73. 2009. https://cpb-us-e1.wpmucdn.com/sites.suffolk.edu/dist/5/1153/files/2018/02/Buteau_10JHTL1-1mkjbhh.pdf.
16. ↑ "Teva Completes Acquisition of Auspex Pharmaceuticals" (in en). 2015-05-05. https://www.tevapharm.com/news-and-media/latest-news/teva-completes-acquisition-of-auspex-pharmaceuticals/.
17. ↑ "First deuterated drug approved". Nature Biotechnology 35 (6): 493–494. June 2017. doi:10.1038/nbt0617-493. PMID 28591114.
18. ↑ "First de novo deuterated drug poised for approval". Nature Reviews. Drug Discovery 21 (9): 623–625. September 2022. doi:10.1038/d41573-022-00139-6. PMID 35974147.
19. ↑ "Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors". Dermatology and Therapy 11 (5): 1763–1776. October 2021. doi:10.1007/s13555-021-00596-8. PMID 34471993.
20. ↑ "U.S. Food and Drug Administration Approves Sotyktu™ (deucravacitinib), Oral Treatment for Adults with Moderate-to-Severe Plaque Psoriasis" (in en). 10 September 2022. https://www.businesswire.com/news/home/20220817005643/en/.
21. ↑ "Interview with the Scientific Founder, President and CEO: Concert Pharmaceuticals, Inc. (CNCE)". The Wall Street Transcript. 2 April 2015. http://www.concertpharma.com/wp-content/uploads/2015/04/WallStreetTranscript-April2015.pdf.
22. ↑ "Deudextromethorphan". AdisInsight. http://adisinsight.springer.com/drugs/800035704.
23. ↑ "Biotech IPOs roll on with Concert's $84M aria". FierceBiotech. February 13, 2014. http://www.fiercebiotech.com/biotech/biotech-ipos-roll-on-concert-s-84m-aria.
24. ↑ "Sun Pharma Completes Acquisition of Concert Pharmaceuticals". www.prnewswire.com (Press release). Retrieved 2024-03-02.
25. ↑ "Vertex News & Events Press Release Details". 6 March 2017. https://investors.vrtx.com/news-releases/news-release-details/vertex-acquire-ctp-656-concert-pharmaceuticals-treatment-cystic.
26. ↑ "Vertex Press Releases, Vertex Announces UK MHRA Approval of Alyftrek (Deutivacaftor/Tezacaftor/Vanzacaftor), a Once-Daily Next-in-Class CFTR Modulator for the Treatment of Cystic Fibrosis". 7 March 2025. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-uk-mhra-approval-alyftrekr.
27. ↑ "Pill of super-protective 'heavy' fat may be key to eternal youth". New Scientist. 13 May 2015. https://www.newscientist.com/article/mg22630214-900-pill-of-super-protective-heavy-fat-may-be-key-to-eternal-youth/.
28. ↑ "RT 001". AdisInsight. http://adisinsight.springer.com/drugs/800042495.
29. ↑ 29.0 29.1 "Poxel Expands Metabolic Pipeline Through Strategic Acquisition Agreement with DeuteRx for DRX-065, a Novel Clinical Stage Drug Candidate for NASH, and Other Programs" (in en-US). 2018-08-30. https://www.poxelpharma.com/en_us/investors/news-events/press-releases/detail/99/poxel-expands-metabolic-pipeline-through-strategic.
30. ↑ 30.0 30.1 "Deuterium-Stabilized (R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity". Hepatology Communications 5 (8): 1412–1425. August 2021. doi:10.1002/hep4.1723. PMID 34430785.
31. ↑ "Deuteropioglitazone dcl, (5R)-". https://pubchem.ncbi.nlm.nih.gov/compound/131634867.
32. ↑ "PXL065 (Deuterium-Stabilized R-Enantiomer of Pioglitazone) Reduces Liver Fat Conent and Improves Liver Histology Without PPARG-Mediated Side Effects in Patients With NASH: Analysis of a 36 Week Placebo-Controlled Phase 2 Trial (DESTINY1)". https://www.aasld.org/the-liver-meeting/pxl065-deuterium-stabilized-r-enantiomer-pioglitazone-reduces-liver-fat-content.
33. ↑ "Salarius Pharmaceuticals Expands Oncology Pipeline Through Strategic Acquisition of Targeted Protein Degradation Portfolio from DeuteRx, LLC". GlobeNewswire News Room (Press release). 2022-01-13. Retrieved 2023-05-23.
34. ↑ "SP-3164, a Novel Cereblon-Binding Protein Degrader, Shows Activity in Preclinical Lymphoma Models". Blood 140: 8865–8866. 2022. doi:10.1182/blood-2022-167495. https://ashpublications.org/blood/article/140/Supplement 1/8865/492443/SP-3164-a-Novel-Cereblon-Binding-Protein-Degrader. Retrieved 2023-05-23.

## Further reading

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