Deuterated drug

Chemical formulae of ethyl linoleate — natural and its deuterated version 11,11-D2-ethyl linoleate (RT001). 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is a small molecule medicinal product in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by its heavier stable isotope deuterium.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]

Mode of action

Hydrogen is a chemical element with an atomic number of 1. It has just one proton and one electron. Deuterium is the heavier naturally occurring, non-radioactive, 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 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.

History

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, 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]

Examples

Deutetrabenazine is a deuterated version of tetrabenazine. It was developed by Teva 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.[13]

Concert Pharmaceuticals focuses on deuterated drugs for various conditions.[14][15][16]

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.[17][18]

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
DRX-065 (d1-(R)-pioglitazone)[19] Phase 1 Stabilize preferred R-enantiomer to obtain mitochondrial function modulation without PPAR-gamma agonist activity (due to S-pioglitazone)
RT001 (d2-linoleic acid ethyl ester) Phase 1/2 Limit lipid peroxidation

References

  1. 1 2 Sanderson K (March 2009). "Big interest in heavy drugs". Nature. 458 (7236): 269. doi:10.1038/458269a. PMID 19295573.
  2. 1 2 Katsnelson A (June 2013). "Heavy drugs draw heavy interest from pharma backers". Nature Medicine. 19 (6): 656. doi:10.1038/nm0613-656. PMID 23744136.
  3. 1 2 3 Gant TG (May 2014). "Using deuterium in drug discovery: leaving the label in the drug". Journal of Medicinal Chemistry. 57 (9): 3595–3611. doi:10.1021/jm4007998. PMID 24294889.
  4. ↑ Bartell LS, Roth EA, Hollowell CD, Kuchitsu K, Young Jr JE (April 1965). "Electron‐Diffraction Study of the Structures of C2H4 and C2D4". The Journal of Chemical Physics. 42 (8): 2683–6. Bibcode:1965JChPh..42.2683B. doi:10.1063/1.1703223.
  5. ↑ Meanwell NA (April 2011). "Synopsis of some recent tactical application of bioisosteres in drug design". Journal of Medicinal Chemistry. 54 (8): 2529–2591. doi:10.1021/jm1013693. PMID 21413808.
  6. ↑ "Drugs that live long will prosper". The Economist. ISSN 0013-0613. Retrieved 2015-09-18.
  7. ↑ Pirali T, Serafini M, Cargnin S, Genazzani AA (June 2019). "Applications of Deuterium in Medicinal Chemistry". Journal of Medicinal Chemistry. 62 (11): 5276–5297. doi:10.1021/acs.jmedchem.8b01808. PMID 30640460.
  8. 1 2 Liu JF, Harbeson SL, Brummel CL, Tung R, Silverman R, Doller D (2017). "A Decade of Deuteration in Medicinal Chemistry". Platform Technologies in Drug Discovery and Validation. Annual Reports in Medicinal Chemistry. Vol. 50. pp. 519–542. doi:10.1016/bs.armc.2017.08.010. ISBN 978-0-12-813069-8.
  9. ↑ Foster AB (1985). "Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design". Advances in Drug Research. 14: 1–40.
  10. ↑ Timmins GS (December 2017). "Deuterated drugs; updates and obviousness analysis". Expert Opinion on Therapeutic Patents. 27 (12): 1353–1361. doi:10.1080/13543776.2017.1378350. PMID 28885861.
  11. ↑ Timmins GS (October 2014). "Deuterated drugs: where are we now?". Expert Opinion on Therapeutic Patents. 24 (10): 1067–1075. doi:10.1517/13543776.2014.943184. PMC 4579527. PMID 25069517.
  12. ↑ Buteau KC (2009). "Deuterated drugs: unexpectedly nonobvious" (PDF). Journal of High Technology Law. 10 (1): 22–73.
  13. ↑ Schmidt C (June 2017). "First deuterated drug approved". Nature Biotechnology. 35 (6): 493–494. doi:10.1038/nbt0617-493. PMID 28591114.
  14. ↑ "Interview with the Scientific Founder, President and CEO: Concert Pharmaceuticals, Inc. (CNCE)" (PDF). The Wall Street Transcript. 2 April 2015.
  15. ↑ "Deudextromethorphan". AdisInsight. Retrieved 16 February 2017.
  16. ↑ Garde D (February 13, 2014). "Biotech IPOs roll on with Concert's $84M aria". FierceBiotech.
  17. ↑ Hamzelou J (13 May 2015). "Pill of super-protective 'heavy' fat may be key to eternal youth". New Scientist.
  18. ↑ "RT 001". AdisInsight. Retrieved 15 January 2018.
  19. ↑ "Deuteropioglitazone dcl, (5R)-". pubchem.ncbi.nlm.nih.gov.

Further reading

Heavy drugs gaining momentum.

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