| 词条 | Deuterated drug | ||||||||||||||||||||||||
| 释义 |
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is a small molecule medicinal product in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by its heavier stable isotope deuterium.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 actionHydrogen 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 the developing anti-bonding orbital of a newly-forming bond). It potentially can result in weaker van der Waals stabilization, and it can produce other changes in properties that are difficult to predict, including changes in the intramolecular volume and the transition state volume.[5] Substituting deuterium for hydrogen yields deuterated compounds that are similar in size and shape to hydrogen-based compounds. HistoryThe first patent in the US granted for deuterated molecules was in the 1970s. Since then patents on deuterated drugs have become more prolific.[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][10][11][12] A number of publications have discussed aspects of intellectual property of deuterated versions of drugs.[13][14][15] ExamplesDeutetrabenazine is a deuterated version of tetrabenazine. It was developed by Teva and approved by the FDA in 2017 as a treatment for 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.[16]Concert Pharmaceuticals focuses on deuterated drugs for various conditions.[17][18][19]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.[20][21]
References1. ^{{cite journal | vauthors = Sanderson K | title = Big interest in heavy drugs | journal = Nature | volume = 458 | issue = 7236 | pages = 269 | date = March 2009 | pmid = 19295573 | doi = 10.1038/458269a }} 2. ^{{cite journal | vauthors = Katsnelson A | title = Heavy drugs draw heavy interest from pharma backers | journal = Nature Medicine | volume = 19 | issue = 6 | pages = 656 | date = June 2013 | pmid = 23744136 | doi = 10.1038/nm0613-656 }} 3. ^{{cite journal | vauthors = Gant TG | title = Using deuterium in drug discovery: leaving the label in the drug | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 9 | pages = 3595–611 | date = May 2014 | pmid = 24294889 | doi = 10.1021/jm4007998 }} 4. ^{{cite journal | vauthors = Bartell LS, Roth EA, Hollowell CD, Kuchitsu K, Young Jr JE | title = Electron‐Diffraction Study of the Structures of C2H4 and C2D4 | journal = The Journal of Chemical Physics | date = April 1965 | volume = 42 | issue = 8 | pages = 2683–6 | doi = 10.1063/1.1703223 | bibcode = 1965JChPh..42.2683B }} 5. ^{{cite journal | vauthors = Gant TG | title = Using deuterium in drug discovery: leaving the label in the drug | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 9 | pages = 3595–611 | date = May 2014 | pmid = 24294889 | doi = 10.1021/jm4007998 }} 6. ^{{Cite news|title = Drugs that live long will prosper|url = https://www.economist.com/news/science-and-technology/21663193-simple-change-some-pharmaceuticals-might-boost-their-efficacy-and-make-few|newspaper = The Economist|access-date = 2015-09-18|issn = 0013-0613}} 7. ^{{cite journal |vauthors=Pirali T, Serafini M, Cargnin S, Genazzani AA |title=Applications of Deuterium in Medicinal Chemistry |journal=J. Med. Chem. |volume= |issue= |pages= |date=January 2019 |pmid=30640460 |doi=10.1021/acs.jmedchem.8b01808 |url=}} 8. ^1 {{cite book |doi=10.1016/bs.armc.2017.08.010 |chapter=A Decade of Deuteration in Medicinal Chemistry |title=Platform Technologies in Drug Discovery and Validation |volume=50 |pages=519–542 |series=Annual Reports in Medicinal Chemistry |year=2017 |last1=Liu |first1=Julie F. |last2=Harbeson |first2=Scott L. |last3=Brummel |first3=Christopher L. |last4=Tung |first4=Roger |last5=Silverman |first5=Robert |last6=Doller |first6=Dario | name-list-format = vanc |isbn=9780128130698 }} 9. ^{{cite journal | vauthors = Foster AB | title = Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design | journal = Advances in Drug Research | date = 1985 | volume = 14 | pages = 1–40 }} 10. ^{{cite journal | vauthors = Sanderson K | title = Big interest in heavy drugs | journal = Nature | volume = 458 | issue = 7236 | pages = 269 | date = March 2009 | pmid = 19295573 | doi = 10.1038/458269a }} 11. ^{{cite journal | vauthors = Katsnelson A | title = Heavy drugs draw heavy interest from pharma backers | journal = Nature Medicine | volume = 19 | issue = 6 | pages = 656 | date = June 2013 | pmid = 23744136 | doi = 10.1038/nm0613-656 }} 12. ^{{cite journal | vauthors = Gant TG | title = Using deuterium in drug discovery: leaving the label in the drug | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 9 | pages = 3595–611 | date = May 2014 | pmid = 24294889 | doi = 10.1021/jm4007998 }} 13. ^{{cite journal | vauthors = Timmins GS | title = Deuterated drugs; updates and obviousness analysis | journal = Expert Opinion on Therapeutic Patents | volume = 27 | issue = 12 | pages = 1353–1361 | date = December 2017 | pmid = 28885861 | doi = 10.1080/13543776.2017.1378350 }} 14. ^{{cite journal | vauthors = Timmins GS | title = Deuterated drugs: where are we now? | journal = Expert Opinion on Therapeutic Patents | volume = 24 | issue = 10 | pages = 1067–75 | date = October 2014 | pmid = 25069517 | pmc = 4579527 | doi = 10.1517/13543776.2014.943184 }} 15. ^{{cite journal | vauthors = Buteau KC |title=Deuterated drugs: unexpectedly nonobvious |journal=Journal of High Technology Law |volume=10 |issue=1 |year=2009 |pages=22–73 |url=https://cpb-us-e1.wpmucdn.com/sites.suffolk.edu/dist/5/1153/files/2018/02/Buteau_10JHTL1-1mkjbhh.pdf }} 16. ^{{cite journal | vauthors = Schmidt C | title = First deuterated drug approved | journal = Nature Biotechnology | volume = 35 | issue = 6 | pages = 493–494 | date = June 2017 | pmid = 28591114 | doi = 10.1038/nbt0617-493 }} 17. ^{{cite news|title=Interview with the Scientific Founder, President and CEO: Concert Pharmaceuticals, Inc. (CNCE)|url=http://www.concertpharma.com/wp-content/uploads/2015/04/WallStreetTranscript-April2015.pdf|work=The Wall Street Transcript|date=2 April 2015}} 18. ^{{cite web|title=Deudextromethorphan|url=http://adisinsight.springer.com/drugs/800035704|publisher=AdisInsight|access-date=16 February 2017 }} 19. ^{{cite news|last1=Garde|first1=Damian | name-list-format = vanc |title=Biotech IPOs roll on with Concert's $84M aria|url=http://www.fiercebiotech.com/biotech/biotech-ipos-roll-on-concert-s-84m-aria|work=FierceBiotech|date=February 13, 2014 }} 20. ^{{cite news|last1=Hamzelou|first1=Jessica | name-list-format = vanc |title=Pill of super-protective ‘heavy’ fat may be key to eternal youth|url=https://www.newscientist.com/article/mg22630214-900-pill-of-super-protective-heavy-fat-may-be-key-to-eternal-youth/|work=New Scientist|date=13 May 2015}} 21. ^{{cite web|title=RT 001|url=http://adisinsight.springer.com/drugs/800042495|publisher=AdisInsight|access-date=15 January 2018 }} Further reading[https://www.chemistryworld.com/feature/2heavy-drugs-gaining-momentum/1010186.article Heavy drugs gaining momentum. ] 2 : Medical isotopes|Deuterated compounds |
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