Deuterium in drug discovery: progress, opportunities and challenges.
Journal
Nature reviews. Drug discovery
ISSN: 1474-1784
Titre abrégé: Nat Rev Drug Discov
Pays: England
ID NLM: 101124171
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
accepted:
12
04
2023
medline:
3
7
2023
pubmed:
6
6
2023
entrez:
5
6
2023
Statut:
ppublish
Résumé
Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a 'deuterium switch' approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.
Identifiants
pubmed: 37277503
doi: 10.1038/s41573-023-00703-8
pii: 10.1038/s41573-023-00703-8
pmc: PMC10241557
doi:
Substances chimiques
Deuterium
AR09D82C7G
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
562-584Informations de copyright
© 2023. Springer Nature Limited.
Références
Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54, 2529–2591 (2011).
pubmed: 21413808
doi: 10.1021/jm1013693
Belleau, B., Burba, J., Pindell, M. & Reiffenstein, J. Effect of deuterium substitution in sympathomimetic amines on adrenergic responses. Science 133, 102–104 (1961).
pubmed: 17769335
doi: 10.1126/science.133.3446.102
Elison, C., Rapoport, H., Laursen, R. & Elliott, H. W. Effect of deuteration of N-CH
pubmed: 13889855
doi: 10.1126/science.134.3485.1078
Agranat, I., Caner, H. & Caldwell, J. Putting chirality to work: the strategy of chiral switches. Nat. Rev. Drug Discov. 1, 753–768 (2002).
pubmed: 12360254
doi: 10.1038/nrd915
Vitale, G. Deuterium drugs attract investment. CEN Glob. Enterp. 101, 10–10 (2023).
doi: 10.1021/cen-10104-buscon1
DeWitt, S. H. & Maryanoff, B. E. Deuterated drug molecules: focus on FDA-approved deutetrabenazine. Biochemistry 57, 472–473 (2018).
pubmed: 29160059
doi: 10.1021/acs.biochem.7b00765
Keam, S. J. & Duggan, S. Donafenib: first approval. Drugs 81, 1915–1920 (2021).
pubmed: 34591285
doi: 10.1007/s40265-021-01603-0
Qian, H.-j et al. Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects. Acta Pharmacol. Sin. 43, 3130–3138 (2022).
pubmed: 35296780
pmcid: 8924727
doi: 10.1038/s41401-022-00895-6
Wrobleski, S. T. et al. Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165. J. Med. Chem. 62, 8973–8995 (2019).
pubmed: 31318208
doi: 10.1021/acs.jmedchem.9b00444
Liu, C. et al. Discovery of BMS-986202: a clinical Tyk2 inhibitor that binds to Tyk2 JH2. J. Med. Chem. 64, 677–694 (2021).
pubmed: 33370104
doi: 10.1021/acs.jmedchem.0c01698
Lesage, A. et al. In vitro pharmacological profile of PHA-022121, a small molecule bradykinin B2 receptor antagonist in clinical development. Int. Immunopharmacol. 105, 108523 (2022).
pubmed: 35086057
doi: 10.1016/j.intimp.2022.108523
Khan, A. J. et al. VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells. Oncotarget 9, 25833–25841 (2018).
pubmed: 29899825
pmcid: 5995231
doi: 10.18632/oncotarget.25383
Harbeson, S. L. & Tung, R. D. Deuterium in drug discovery and development. Annu. Rep. Med. Chem. 46, 403–417 (2011).
Gant, T. G. Using deuterium in drug discovery: leaving the label in the drug. J. Med. Chem. 57, 3595–3611 (2014).
pubmed: 24294889
doi: 10.1021/jm4007998
Liu, J. F. et al. in Platform Technologies in Drug Discovery and Validation (ed. Goodnow, R. A.) 519–542 (Academic, 2017). [Series Ed. Neidle, S. Annual Reports in Medicinal Chemistry Vol. 50].
Pirali, T., Serafini, M., Cargnin, S. & Genazzani, A. A. Applications of deuterium in medicinal chemistry. J. Med. Chem. 62, 5276–5297 (2019).
pubmed: 30640460
doi: 10.1021/acs.jmedchem.8b01808
Cargnin, S., Serafini, M. & Pirali, T. A primer of deuterium in drug design. Future Med. Chem. 11, 2039–2042 (2019).
pubmed: 31538524
doi: 10.4155/fmc-2019-0183
Brunning, A. Periodic graphics: the science and uses of deuterium (Poster). Chem. Eng. News https://cen.acs.org/physical-chemistry/Periodic-Graphics-science-uses-deuterium/99/i43 (2021).
Baillie, T. A. The use of stable isotopes in pharmacological research. Pharmacol. Rev. 33, 81–132 (1981).
pubmed: 7029573
Atzrodt, J., Derdau, V., Kerr, W. J. & Reid, M. Deuterium- and tritium-labelled compounds: applications in the life sciences. Angew. Chem. Int. Ed. Engl. 57, 1758–1784 (2018).
pubmed: 28815899
doi: 10.1002/anie.201704146
Urey, H. C., Brickwedde, F. G. & Murphy, G. M. A Hydrogen isotope of mass 2. Phys. Rev. 39, 164–165 (1932).
doi: 10.1103/PhysRev.39.164
Gharibi, H. et al. Abnormal (hydroxy)proline deuterium content redefines hydrogen chemical mass. J. Am. Chem. Soc. 144, 2484–2487 (2022).
pubmed: 35107291
pmcid: 8855419
doi: 10.1021/jacs.1c12512
Jones, P. J. & Leatherdale, S. T. Stable isotopes in clinical research: safety reaffirmed. Clin. Sci. 80, 277–280 (1991).
doi: 10.1042/cs0800277
Koletzko, B., Sauerwald, T. & Demmelmair, H. Safety of stable isotope use. Eur. J. Pediatr. 156, S12–S17 (1997).
pubmed: 9266209
doi: 10.1007/PL00014267
Scheiner, S. & Čuma, M. Relative stability of hydrogen and deuterium bonds. J. Am. Chem. Soc. 118, 1511–1521 (1996).
doi: 10.1021/ja9530376
Wiberg, K. B. The deuterium isotope effect. Chem. Rev. 55, 713–743 (1955).
doi: 10.1021/cr50004a004
Bell, R. P. Recent advances in the study of kinetic hydrogen isotope effects. Chem. Soc. Rev. 3, 513–544 (1974).
doi: 10.1039/cs9740300513
Krumbiegel, P. Large deuterium isotope effects and their use: a historical review. Isot. Environ. Health Stud. 47, 1–17 (2011).
doi: 10.1080/10256016.2011.556725
Gjervig Jensen, K., Tornby Christoffersen, C., Graulund Hvenegaard, M., Didriksen, M. & Jørgensen, M. Distal kinetic deuterium isotope effect: phenyl ring deuteration attenuates N-demethylation of Lu AF35700. Bioorg. Med. Chem. Lett. 72, 128879 (2022).
pubmed: 35809818
doi: 10.1016/j.bmcl.2022.128879
Furge, L. L. & Guengerich, F. P. Cytochrome P450 enzymes in drug metabolism and chemical toxicology: an introduction. Biochem. Mol. Biol. Educ. 34, 66–74 (2006).
pubmed: 21638641
doi: 10.1002/bmb.2006.49403402066
Nelson, S. D. & Trager, W. F. The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab. Dispos. 31, 1481–1498 (2003).
pubmed: 14625345
doi: 10.1124/dmd.31.12.1481
Guengerich, F. P. Kinetic deuterium isotope effects in cytochrome P450 reactions. Methods Enzymol. 596, 217–238 (2017).
pubmed: 28911772
pmcid: 5776663
doi: 10.1016/bs.mie.2017.06.036
Johnson, K., Le, H. & Khojasteh, S. C. in Identification and Quantification of Drugs, Metabolites, Drug Metabolizing Enzymes, and Transporters (2nd edn) (eds Ma, S. & Chowdhury, S. K.) 439–460 (Elsevier, 2020).
Horning, M. G., Haegele, K. D., Sommer, K. R., Nowlin, J. & Stafford, M. Metabolic Switching of Drug Pathways as a Consequence of Deuterium Substitution (OSTI, 1975).
Regal, K. A., Kunze, K. L., Peter, R. M. & Nelson, S. D. Oxidation of caffeine by CYP1A2: isotope effects and metabolic switching. Drug. Metab. Dispos. 33, 1837–1844 (2005).
pubmed: 16135658
Benchekroun, Y., Dautraix, S., Desage, M. & Brazier, J. L. Deuterium isotope effects on caffeine metabolism. Eur. J. Drug Metab. Pharmacokinet. 22, 127–133 (1997).
pubmed: 9248780
doi: 10.1007/BF03189795
Parente, R. M., Tarantino, P. M., Sippy, B. C. & Burdock, G. A. Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine. Food Chem. Toxicol. 160, 112774 (2022).
pubmed: 34974129
doi: 10.1016/j.fct.2021.112774
Sherman, M. M. et al. A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d
pubmed: 35690181
doi: 10.1016/j.yrtph.2022.105194
Bechalany, A. et al. Isotope effects on the lipophilicity of deuterated caffeines. Helv. Chim. Acta 72, 472–476 (1989).
doi: 10.1002/hlca.19890720308
Cherrah, Y. et al. Study of deuterium isotope effects on protein binding by gas chromatography/mass spectrometry. Caffeine and deuterated isotopomers. Biomed. Environ. Mass. Spectrom. 14, 653–657 (1987).
pubmed: 2962673
doi: 10.1002/bms.1200141115
Pang, X., Peng, L. & Chen, Y. Effect of N-methyl deuteration on pharmacokinetics and pharmacodynamics of enzalutamide. J. Label. Compd. Radiopharm. 60, 401–409 (2017).
doi: 10.1002/jlcr.3516
Li, X. et al. Phase I clinical trial of HC-1119: a deuterated form of enzalutamide. Int. J. Cancer 149, 1473–1482 (2021).
pubmed: 34109624
doi: 10.1002/ijc.33706
Bardin, E. et al. Modulators of CFTR. Updates on clinical development and future directions. Eur. J. Med. Chem. 213, 113195 (2021).
pubmed: 33524685
doi: 10.1016/j.ejmech.2021.113195
Garnock-Jones, K. P. Dextromethorphan/quinidine: in pseudobulbar affect. CNS Drugs 25, 435–445 (2011).
pubmed: 21476614
doi: 10.2165/11207260-000000000-00000
Garay, R. P. & Grossberg, G. T. AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type. Expert Opin. Investig. Drugs 26, 121–132 (2017).
pubmed: 27936965
doi: 10.1080/13543784.2017.1267726
Wilkinson, S. T. & Sanacora, G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug. Discov. Today 24, 606–615 (2019).
pubmed: 30447328
doi: 10.1016/j.drudis.2018.11.007
Khoury, R. et al. AVP-786 as a promising treatment option for Alzheimer’s disease including agitation. Expert Opin. Pharmacother. 22, 783–795 (2021).
pubmed: 33615952
doi: 10.1080/14656566.2021.1882995
Khozin, S. et al. Osimertinib for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer. Clin. Cancer Res. 23, 2131–2135 (2017).
pubmed: 27923840
doi: 10.1158/1078-0432.CCR-16-1773
Dickinson, P. A. et al. Metabolic disposition of osimertinib in rats, dogs, and humans: insights into a drug designed to bind covalently to a cysteine residue of epidermal growth factor receptor. Drug Metab. Dispos. 44, 1201–1212 (2016).
pubmed: 27226351
doi: 10.1124/dmd.115.069203
Meng, Y. et al. Discovery of dosimertinib, a highly potent, selective, and orally efficacious deuterated EGFR targeting clinical candidate for the treatment of non-small-cell lung cancer. J. Med. Chem. 64, 925–937 (2021).
pubmed: 33459024
doi: 10.1021/acs.jmedchem.0c02005
Ghanayem, B. I., Burka, L. T. & Matthews, H. B. Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases. J. Pharmacol. Exp. Ther. 242, 222–231 (1987).
pubmed: 3612528
Schneider, F. et al. Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects. Br. J. Clin. Pharmacol. 84, 2422–2432 (2018).
pubmed: 29959802
pmcid: 6138493
doi: 10.1111/bcp.13702
Pestov, N. B. et al. Control of lysyl oxidase activity through site-specific deuteration of lysine. Bioorg. Med. Chem. Lett. 21, 255–258 (2011).
pubmed: 21106372
doi: 10.1016/j.bmcl.2010.11.018
Blum, E. et al. Rational alteration of pharmacokinetics of chiral fluorinated and deuterated derivatives of emixustat for retinal therapy. J. Med. Chem. 64, 8287–8302 (2021).
pubmed: 34081480
pmcid: 8381290
doi: 10.1021/acs.jmedchem.1c00279
Manevski, N., King, L., Pitt, W. R., Lecomte, F. & Toselli, F. Metabolism by aldehyde oxidase: drug design and complementary approaches to challenges in drug discovery. J. Med. Chem. 62, 10955–10994 (2019).
pubmed: 31385704
doi: 10.1021/acs.jmedchem.9b00875
Lolkema, M. P. et al. The c-Met tyrosine kinase inhibitor JNJ-38877605 causes renal toxicity through species-specific insoluble metabolite formation. Clin. Cancer Res. 21, 2297–2304 (2015).
pubmed: 25745036
pmcid: 4433755
doi: 10.1158/1078-0432.CCR-14-3258
Zhan, Z., Peng, X., Sun, Y., Ai, J. & Duan, W. Evaluation of deuterium-labeled JNJ38877605: pharmacokinetic, metabolic, and in vivo antitumor profiles. Chem. Res. Toxicol. 31, 1213–1218 (2018).
pubmed: 30284817
doi: 10.1021/acs.chemrestox.8b00191
DeWitt, S., Czarnik, A. W. & Jacques, V. Deuterium-enabled chiral switching (DECS) yields chirally pure drugs from chemically interconverting racemates. ACS Med. Chem. Lett. 11, 1789–1792 (2020).
pubmed: 33062153
pmcid: 7549104
doi: 10.1021/acsmedchemlett.0c00052
Maltais, F. et al. In vitro and in vivo isotope effects with hepatitis C protease inhibitors: enhanced plasma exposure of deuterated telaprevir versus telaprevir in rats. J. Med. Chem. 52, 7993–8001 (2009).
pubmed: 19894743
doi: 10.1021/jm901023f
Jacques, V., Czarnik, A. W., Judge, T. M., Van der Ploeg, L. H. T. & DeWitt, S. H. Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs. Proc. Natl Acad. Sci. USA 112, E1471–E1479 (2015).
pubmed: 25775521
pmcid: 4378388
doi: 10.1073/pnas.1417832112
Jacques, V. et al. Deuterium-stabilized (R)-pioglitazone (PXL065) is responsible for pioglitazone efficacy in NASH yet exhibits little to no PPARγ activity. Hepatol. Commun. 5, 1412–1425 (2021).
pubmed: 34430785
pmcid: 8369945
doi: 10.1002/hep4.1723
Monternier, P.-A. et al. Therapeutic potential of deuterium-stabilized (R)-pioglitazone — PXL065 — for X-linked adrenoleukodystrophy. J. Inherit. Metab. Dis. 45, 832–847 (2022).
pubmed: 35510808
pmcid: 9545763
doi: 10.1002/jimd.12510
Jansen-van Vuuren, R. D., Jedlovčnik, L., Košmrlj, J., Massey, T. E. & Derdau, V. Deuterated drugs and biomarkers in the COVID-19 pandemic. ACS Omega 7, 41840–41858 (2022).
pubmed: 36440130
pmcid: 9685803
doi: 10.1021/acsomega.2c04160
Quan, B.-X. et al. An orally available M
pubmed: 35477751
doi: 10.1038/s41564-022-01119-7
Charbel Issa, P., Barnard, A. R., Herrmann, P., Washington, I. & MacLaren, R. E. Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. Proc. Natl Acad. Sci. USA 112, 8415–8420 (2015).
pubmed: 26106163
pmcid: 4500285
doi: 10.1073/pnas.1506960112
Kaufman, Y., Ma, L. & Washington, I. Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin A dimers in wild-type rodents. J. Biol. Chem. 286, 7958–7965 (2011).
pubmed: 21075840
doi: 10.1074/jbc.M110.178640
Saad, L., & Washington, I. Can vitamin A be improved to prevent blindness due to age-related macular degeneration, Stargardt disease and other retinal dystrophies? Adv. Exp. Med. Biol. 854, 355–361 (2016).
pubmed: 26427432
doi: 10.1007/978-3-319-17121-0_47
Brenna, J. T. et al. Plasma and red blood cell membrane accretion and pharmacokinetics of RT001 (bis-allylic 11,11-D2-linoleic acid ethyl ester) during long term dosing in patients. J. Pharm. Sci. 109, 3496–3503 (2020).
pubmed: 32871154
doi: 10.1016/j.xphs.2020.08.019
Zesiewicz, T. et al. Randomized, clinical trial of RT001: early signals of efficacy in Friedreich’s ataxia. Mov. Disord. 33, 1000–1005 (2018).
pubmed: 29624723
doi: 10.1002/mds.27353
Angelova, P. R. et al. RT001 in progressive supranuclear palsy — clinical and in-vitro observations. Antioxidants 10, 1021 (2021).
pubmed: 34202031
pmcid: 8300819
doi: 10.3390/antiox10071021
Ben Abu, N. et al. Sweet taste of heavy water. Commun. Biol. 4, 440 (2021).
pubmed: 33824405
pmcid: 8024362
doi: 10.1038/s42003-021-01964-y
Urey, H. C. & Failla, G. Concerning the taste of heavy water. Science 81, 273–273 (1935).
pubmed: 17811065
doi: 10.1126/science.81.2098.273.b
Belz, T. F. et al. Enhancement of a heroin vaccine through hapten deuteration. J. Am. Chem. Soc. 142, 13294–13298 (2020).
pubmed: 32700530
pmcid: 7544008
doi: 10.1021/jacs.0c05219
Timmins, G. S. Deuterated drugs; updates and obviousness analysis. Expert Opin. Ther. Pat. 27, 1353–1361 (2017).
pubmed: 28885861
doi: 10.1080/13543776.2017.1378350
Schmidt, C. First deuterated drug approved. Nat. Biotechnol. 35, 493–494 (2017).
pubmed: 28591114
doi: 10.1038/nbt0617-493
Hayden, M. R., Leavitt, B. R., Yasothan, U. & Kirkpatrick, P. Tetrabenazine. Nat. Rev. Drug Discov. 8, 17–18 (2009).
pubmed: 19116624
doi: 10.1038/nrd2784
Schneider, F. et al. Pharmacokinetic and metabolic profile of deutetrabenazine (TEV-50717) compared with tetrabenazine in healthy volunteers. Clin. Transl. Sci. 13, 707–717 (2020).
pubmed: 32155315
pmcid: 7359938
doi: 10.1111/cts.12754
Schneider, F. et al. Pharmacokinetics of deutetrabenazine and tetrabenazine: dose proportionality and food effect. Clin. Pharmacol. Drug Dev. 10, 647–659 (2021).
pubmed: 33038289
doi: 10.1002/cpdd.882
Gupta, H. et al. Deutetrabenazine for the treatment of chorea associated with Huntington’s disease. Health Psychol. Res. 10, 36040 (2022).
pubmed: 35774908
pmcid: 9239349
doi: 10.52965/001c.36040
Coffey, B. et al. Efficacy and safety of fixed-dose deutetrabenazine in children and adolescents for tics associated with Tourette syndrome: a randomized clinical trial. JAMA Netw. Open 4, e2129397 (2021).
pubmed: 34661664
pmcid: 8524312
doi: 10.1001/jamanetworkopen.2021.29397
Jankovic, J. et al. Safety and efficacy of flexible-dose deutetrabenazine in children and adolescents with Tourette syndrome: a randomized clinical trial. JAMA Netw. 4, e2128204 (2021).
doi: 10.1001/jamanetworkopen.2021.28204
Group, H. S. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. J. Am. Med. Assoc. 316, 40–50 (2016).
doi: 10.1001/jama.2016.8655
Frank, S. et al. Safety of converting from tetrabenazine to deutetrabenazine for the treatment of chorea. JAMA Neurol. 74, 977–982 (2017).
pubmed: 28692723
pmcid: 5710322
doi: 10.1001/jamaneurol.2017.1352
Rodrigues, F. B. & Wild, E. J. Huntington’s disease clinical trials corner: February 2018. J. Huntingt. Dis. 7, 89–98 (2018).
doi: 10.3233/JHD-189001
Hauser, R. A. et al. Long-term deutetrabenazine treatment for tardive dyskinesia is associated with sustained benefits and safety: a 3-year, open-label extension study. Front. Neurol. 13, 773999 (2022).
pubmed: 35280262
pmcid: 8906841
doi: 10.3389/fneur.2022.773999
Anderson, K. E. et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry 4, 595–604 (2017).
pubmed: 28668671
doi: 10.1016/S2215-0366(17)30236-5
Fernandez, H. H. et al. Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia. J. Neurol. Neurosurg. Psychiatry 90, 1317–1323 (2019).
pubmed: 31296586
Claassen, D. O. et al. Indirect tolerability comparison of deutetrabenazine and etrabenazine for Huntington disease. J. Clin. Mov. Disord. 4, 3 (2017).
pubmed: 28265459
pmcid: 5331691
doi: 10.1186/s40734-017-0051-5
Claassen, D. O. et al. Real-world adherence to tetrabenazine or deutetrabenazine among patients with Huntington’s disease: a retrospective database analysis. Neurol. Ther. 11, 435–448 (2022).
pubmed: 34905160
doi: 10.1007/s40120-021-00309-5
Rodrigues, F. B., Duarte, G. S., Costa, J., Ferreira, J. J. & Wild, E. J. Tetrabenazine versus deutetrabenazine for Huntington’s disease: twins or distant cousins? Mov. Disord. Clin. Pract. 4, 582–585 (2017).
pubmed: 28920068
pmcid: 5573977
doi: 10.1002/mdc3.12483
Rodrigues, F. B., Duarte, G. S., Costa, J., Ferreira, J. J. & Wild, E. J. Meta-research metrics matter: letter regarding article “indirect tolerability comparison of deutetrabenazine and tetrabenazine for Huntington disease”. J. Clin. Mov. Disord. 4, 19 (2017).
pubmed: 29201386
pmcid: 5698972
doi: 10.1186/s40734-017-0067-x
US DHHS, FDA, CDER. Guidance for Industry: Applications covered by Section 505(b)2 https://www.fda.gov/media/72419/download (1999).
Freije, I., Lamouche, S. & Tanguay, M. Review of drugs approved via the 505(b)(2) pathway: uncovering drug development trends and regulatory requirements. Ther. Innov. Regul. Sci. 54, 128–138 (2020).
pubmed: 32008242
doi: 10.1007/s43441-019-00036-y
Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 6 (2021).
pubmed: 33479224
doi: 10.1038/s41572-020-00240-3
Liu, J. et al. Safety, pharmacokinetics and efficacy of donafenib in treating advanced hepatocellular carcinoma: report from a phase 1b trial. Pharmazie 74, 688–693 (2019).
pubmed: 31739839
Li, X. et al. A phase I dose-escalation, pharmacokinetics and food-effect study of oral donafenib in patients with advanced solid tumours. Cancer Chemother. Pharmacol. 85, 593–604 (2020).
pubmed: 32008115
doi: 10.1007/s00280-020-04031-1
Qin, S. et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase II–III trial. J. Clin. Oncol. 39, 3002–3011 (2021).
pubmed: 34185551
pmcid: 8445562
doi: 10.1200/JCO.21.00163
Li, Q. & Zhu, H. Donafenib treatment for hepatocellular carcinoma: a case report. Medicine 100, e26373 (2021).
pubmed: 34160411
pmcid: 8238319
doi: 10.1097/MD.0000000000026373
Meng, R., Cao, Y., Zhou, T., Hu, H. & Qiu, Y. The cost effectiveness of donafenib compared with sorafenib for the first-line treatment of unresectable or metastatic hepatocellular carcinoma in China. Front. Public Health 10, 794131 (2022).
pubmed: 35433574
pmcid: 9008355
doi: 10.3389/fpubh.2022.794131
Kokic, G. et al. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nat. Commun. 12, 279 (2021).
pubmed: 33436624
pmcid: 7804290
doi: 10.1038/s41467-020-20542-0
Mehellou, Y., Rattan, H. S. & Balzarini, J. The ProTide prodrug technology: from the concept to the clinic. J. Med. Chem. 61, 2211–2226 (2018).
pubmed: 28792763
doi: 10.1021/acs.jmedchem.7b00734
Xie, J. & Wang, Z. Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment. Acta Pharm. Sin. B 11, 1607–1616 (2021).
pubmed: 34221871
pmcid: 8245906
doi: 10.1016/j.apsb.2021.03.028
Xie, Y. et al. Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2. Cell Res. 31, 1212–1214 (2021).
pubmed: 34584244
pmcid: 8477624
doi: 10.1038/s41422-021-00570-1
Shen, Y. et al. An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 Omicron variants. Emerg. Microbes Infect. 11, 1518–1523 (2022).
pubmed: 35579892
pmcid: 9176639
doi: 10.1080/22221751.2022.2078230
Zhang, R. et al. Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model. Signal Transduct. Target. Ther. 7, 123 (2022).
pubmed: 35429988
pmcid: 9012943
doi: 10.1038/s41392-022-00963-7
Chessari, G. et al. Structure-based design of potent and orally active isoindolinone inhibitors of MDM2-p53 protein–protein interaction. J. Med. Chem. 64, 4071–4088 (2021).
pubmed: 33761253
doi: 10.1021/acs.jmedchem.0c02188
Purushottamachar, P., Thomas, E., Thankan, R. S. & Njar, V. C. O. Novel deuterated Mnk1/2 protein degrader VNLG-152R analogs: synthesis, in vitro anti-TNBC activities and pharmacokinetics in mice. Eur. J. Med. Chem. 238, 114441 (2022).
pubmed: 35617854
doi: 10.1016/j.ejmech.2022.114441
Dampalla, C. S. et al. Structure-guided design of potent inhibitors of SARS-CoV-2 3CL protease: structural, biochemical, and cell-based studies. J. Med. Chem. 64, 17846–17865 (2021).
pubmed: 34865476
doi: 10.1021/acs.jmedchem.1c01037
Dampalla, C. S. et al. Structure-guided design of potent spirocyclic inhibitors of severe acute respiratory syndrome coronavirus-2 3C-like protease. J. Med. Chem. 65, 7818–7832 (2022).
pubmed: 35638577
pmcid: 9172056
doi: 10.1021/acs.jmedchem.2c00224
Turcu, A. L. et al. Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer’s disease. Eur. J. Med. Chem. 236, 114354 (2022).
pubmed: 35453065
pmcid: 9106868
doi: 10.1016/j.ejmech.2022.114354
Yang, T. et al. Identification of a novel 2,8-diazaspiro[4.5]decan-1-one derivative as a potent and selective dual TYK2/JAK1 inhibitor for the treatment of inflammatory bowel disease. J. Med. Chem. 65, 3151–3172 (2022).
pubmed: 35113547
doi: 10.1021/acs.jmedchem.1c01137
King, B. et al. A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results. J. Am. Acad. Dermatol. 85, 379–387 (2021).
pubmed: 33757798
doi: 10.1016/j.jaad.2021.03.050
Liu, L. et al. Design and evaluation of [
pubmed: 36548390
doi: 10.1021/acs.jmedchem.2c01585
Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 16, 843–862 (2017).
pubmed: 29104284
doi: 10.1038/nrd.2017.201
Attwood, M. M., Fabbro, D., Sokolov, A. V., Knapp, S. & Schiöth, H. B. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat. Rev. Drug Discov. 20, 839–861 (2021).
pubmed: 34354255
doi: 10.1038/s41573-021-00252-y
Kragstrup, T. W. et al. Waiting for JAK inhibitor safety data. RDM Open 8, e002236 (2022).
Nogueira, M., Puig, L. & Torres, T. JAK inhibitors for treatment of psoriasis: focus on selective TYK2 inhibitors. Drugs 80, 341–352 (2020).
pubmed: 32020553
doi: 10.1007/s40265-020-01261-8
Jo, C. E., Gooderham, M. & Beecker, J. TYK 2 inhibitors for the treatment of dermatologic conditions: the evolution of JAK inhibitors. Int. J. Dermatol. 61, 139–147 (2022).
pubmed: 33929045
doi: 10.1111/ijd.15605
Dendrou, C. A. et al. Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci. Transl. Med. 8, 363ra149 (2016).
pubmed: 27807284
pmcid: 5737835
doi: 10.1126/scitranslmed.aag1974
Schlapbach, C. & Conrad, C. TYK-ing all the boxes in psoriasis. J. Allergy Clin. Immunol. 149, 1936–1939 (2022).
pubmed: 35341877
doi: 10.1016/j.jaci.2022.03.014
Catlett, I. M. et al. Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis. J. Allergy Clin. Immunol. 149, 2010–2020.e8 (2022).
pubmed: 34767869
doi: 10.1016/j.jaci.2021.11.001
Burke, J. R. et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci. Transl. Med. 11, eaaw1736 (2019).
pubmed: 31341059
doi: 10.1126/scitranslmed.aaw1736
Catlett, I. et al. SAT0226. A first-in-human, study of BMS-986165, a selective, potent, allosteric small molecule inhibitor of tyrosine kinase 2. Ann. Rheum. Dis. 76, 859 (2017).
Papp, K. et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N. Engl. J. Med. 379, 1313–1321 (2018).
pubmed: 30205746
doi: 10.1056/NEJMoa1806382
Thaçi, D. et al. Deucravacitinib in moderate to severe psoriasis: clinical and quality-of-life outcomes in a phase 2 trial. Dermatol. Ther. 12, 495–510 (2022).
doi: 10.1007/s13555-021-00649-y
Chimalakonda, A. et al. Lack of electrocardiographic effects of deucravacitinib in healthy subjects. Clin. Pharmacol. Drug Dev. 11, 442–453 (2022).
pubmed: 35182043
pmcid: 9306920
doi: 10.1002/cpdd.1056
Strober, B. et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 POETYK PSO-2 trial. J. Am. Acad. Dermatol. 88, 29–39 (2023).
pubmed: 35820547
doi: 10.1016/j.jaad.2022.08.061
Winthrop, K. L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol. 13, 234–243 (2017).
pubmed: 28250461
doi: 10.1038/nrrheum.2017.23
Mullard, A. First de novo deuterated drug poised for approval. Nat. Rev. Drug Discov. 21, 623–625 (2022).
pubmed: 35974147
doi: 10.1038/d41573-022-00139-6
Mease, P. J. et al. Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann. Rheum. Dis. 81, 815–822 (2022).
pubmed: 35241426
doi: 10.1136/annrheumdis-2021-221664
Hannon, C. W., McCourt, C., Lima, H. C., Chen, S. & Bennett, C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst. Rev. 3, CD007478 (2021).
pubmed: 33687069
King, Brett et al. Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus kinase inhibitor, in moderate-to-severe alopecia areata. J. Am. Acad. Dermatol. 87, 306–313 (2022).
pubmed: 35364216
doi: 10.1016/j.jaad.2022.03.045
Zuraw, B. L. HAE therapies: past present and future. Allergy Asthma Clin. Immunol. 6, 23 (2010).
pubmed: 20667126
pmcid: 2921104
doi: 10.1186/1710-1492-6-23
Lesage, A., Loenders, B. & Knolle, J. PHA-022121, a first in class oral bradykinin B2 receptor antagonist in clinical development: proof of concept study in a translational monkey bradykinin challenge model. J. Allergy Clin. Immunol. 145, AB346 (2020).
doi: 10.1016/j.jaci.2019.12.094
Timme, C. R., Rath, B. H., O’Neill, J. W., Camphausen, K. & Tofilon, P. J. The DNA-PK inhibitor VX-984 enhances the radiosensitivity of glioblastoma cells grown in vitro and as orthotopic xenografts. Mol. Cancer Ther. 17, 1207–1216 (2018).
pubmed: 29549168
pmcid: 6322200
doi: 10.1158/1535-7163.MCT-17-1267
Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 61, 5822–5880 (2018).
pubmed: 29400967
doi: 10.1021/acs.jmedchem.7b01788
Pan, Y. The darck of fluorine. ACS Med. Chem. Lett. 10, 1016–1019 (2019).
pubmed: 31312400
pmcid: 6627733
doi: 10.1021/acsmedchemlett.9b00235
Han, J. et al. Chemical aspects of human and environmental overload with fluorine. Chem. Rev. 121, 4678–4742 (2021).
pubmed: 33723999
pmcid: 8945431
doi: 10.1021/acs.chemrev.0c01263
Wang, X.-M. et al. Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone. Drug. Metab. Pharmacokinet. 47, 100477 (2022).
pubmed: 36368298
doi: 10.1016/j.dmpk.2022.100477
Sun, L.-Q. et al. Discovery of BMS-986144, a third-generation, pan-genotype NS3/4A protease inhibitor for the treatment of hepatitis C virus infection. J. Med. Chem. 63, 14740–14760 (2020).
pubmed: 33226226
doi: 10.1021/acs.jmedchem.0c01296
Spock, M. et al. Discovery of VU6028418: a highly selective and orally bioavailable M4 muscarinic acetylcholine receptor antagonist. ACS Med. Chem. Lett. 12, 1342–1349 (2021).
pubmed: 34413964
pmcid: 8366002
doi: 10.1021/acsmedchemlett.1c00363
Xu, Z. et al. Evaluation of efficacy and safety after replacement of methyl hydrogen with deuterium at methyl formate of clopidogrel. Eur. J. Pharm. Sci. 172, 106157 (2022).
pubmed: 35257876
doi: 10.1016/j.ejps.2022.106157
Shvartsbart, A. et al. Discovery of potent and selective inhibitors of wild-type and gatekeeper mutant fibroblast growth factor receptor (FGFR) 2/3. J. Med. Chem. 65, 15433–15442 (2022).
pubmed: 36356320
doi: 10.1021/acs.jmedchem.2c01366
Zhu, Y., Zhou, J. & Jiao, B. Deuterated clopidogrel analogues as a new generation of antiplatelet agents. ACS Med. Chem. Lett. 4, 349–352 (2013).
pubmed: 24900671
pmcid: 4027567
doi: 10.1021/ml300460t
Aprile, S. et al. An unexpected deuterium-induced metabolic switch in doxophylline. ACS Med. Chem. Lett. 13, 1278–1285 (2022).
pubmed: 35978700
pmcid: 9377007
doi: 10.1021/acsmedchemlett.2c00166
Marcucci, F., Mussoni, E., Martelli, P., Guaitani, A. & Garattini, S. Metabolism and anticonvulsant activity of deuterated N-demethyldiazepam. J. Pharm. Sci. 62, 1900–1902 (1973).
pubmed: 4148451
doi: 10.1002/jps.2600621144
Liu, X. et al. Deuteration of the farnesyl terminal methyl groups of δ-tocotrienol and its effects on the metabolic stability and ability of inducing G-CSF production. Bioorg. Med. Chem. 28, 115498 (2020).
pubmed: 32291146
pmcid: 7433030
doi: 10.1016/j.bmc.2020.115498
Helfenbein, J. et al. Isotopic effect study of propofol deuteration on the metabolism, activity, and toxicity of the anesthetic. J. Med. Chem. 45, 5806–5808 (2002).
pubmed: 12477364
doi: 10.1021/jm020864q
Manley, P. W., Blasco, F., Mestan, J. & Aichholz, R. The kinetic deuterium isotope effect as applied to metabolic deactivation of imatinib to the des-methyl metabolite, CGP74588. Bioorg. Med. Chem. 21, 3231–3239 (2013).
pubmed: 23611771
doi: 10.1016/j.bmc.2013.03.038
Vang, Z. P. et al. Copper-catalyzed transfer hydrodeuteration of aryl alkenes with quantitative isotopomer purity analysis by molecular rotational resonance spectroscopy. J. Am. Chem. Soc. 143, 7707–7718 (2021).
pubmed: 34000182
doi: 10.1021/jacs.1c00884
Czeskis, B. et al. Deuterated active pharmaceutical ingredients: a science-based proposal for synthesis, analysis, and control. Part 1: framing the problem. J. Label. Compd. Radiopharm. 62, 690–694 (2019).
doi: 10.1002/jlcr.3743
ICH. Impurities in new drug substrates Q3A(R2). ICH Harmonised Tripartite Guideline https://database.ich.org/sites/default/files/Q3A%28R2%29%20Guideline.pdf (2006).
Serafini, M. et al. What’s in a name? Drug nomenclature and medicinal chemistry trends using INN publications. J. Med. Chem. 64, 4410–4429 (2021).
pubmed: 33847110
pmcid: 8154580
doi: 10.1021/acs.jmedchem.1c00181
World Health Organization. Executive summary. INN Working Doc. 21.533 WHO https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/73rd_executive_summary.pdf (2021).
Karkhanis, A. V. et al. Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts. Acta Pharm. Sin. B 12, 3905–3923 (2022).
pubmed: 36213535
pmcid: 9532722
doi: 10.1016/j.apsb.2022.03.008
Tang, L. W. T., Lim, R. Y. R., Venkatesan, G. & Chan, E. C. Y. Rational deuteration of dronedarone attenuates its toxicity in human hepatic HepG2 cells. Toxicol. Res. 11, 311–324 (2022).
doi: 10.1093/toxres/tfac017
Kambayashi, R. et al. An exploratory analysis of effects of poyendarone, a deuterated analogue of dronedarone, on the canine model of paroxysmal atrial fibrillation. Naunyn Schmiedebergs Arch. Pharmacol. 394, 1103–1112 (2021).
pubmed: 33427928
doi: 10.1007/s00210-020-02047-1
Marks, M., & Cohen, I. G. Patents on psychedelics: the next legal battlefront of drug development. Harv. Law Rev. Forum 135, 212–35 (2022).
Kargbo, R. B. Psilocybin therapeutic research: the present and future paradigm. ACS Med. Chem. Lett. 11, 399–402 (2020).
pubmed: 32292538
pmcid: 7153026
doi: 10.1021/acsmedchemlett.0c00048
Kargbo, R. B. Application of deuterated N,N-dimethyltryptamine in the potential treatment of psychiatric and neurological disorders. ACS Med. Chem. Lett. 13, 1402–1404 (2022).
pubmed: 36105328
doi: 10.1021/acsmedchemlett.2c00354
Timmins, G. S. Deuterated drugs: where are we now? Expert Opin. Ther. Pat. 24, 1067–1075 (2014).
pubmed: 25069517
pmcid: 4579527
doi: 10.1517/13543776.2014.943184
Buteau, K. C. Deuterated drugs: unexpectedly nonobvious? J. High Tech. L. 10, 22 (2010).
Furrow, M., & Austin, E. Protecting deuterated drugs. Intellectual Property Magazine 35–36 https://www.venable.com/-/media/035_036ipm_february_2018fo1.pdf (Feb 2018).
Li, L., Jakowski, J., Do, C. & Hong, K. Deuteration and polymers: rich history with great potential. Macromolecules 54, 3555–3584 (2021).
doi: 10.1021/acs.macromol.0c02284
Tullo, A. H. Your next TV could contain uncommon isotopes. CEN Glob. Enterp. 100, 21–22 (2022).
doi: 10.1021/cen-10009-feature1
Grimm, J. B. et al. A general method to improve fluorophores using deuterated auxochromes. JACS Au 1, 690–696 (2021).
pubmed: 34056637
pmcid: 8154212
doi: 10.1021/jacsau.1c00006
Roßmann, K. et al. N-methyl deuterated rhodamines for protein labelling in sensitive fluorescence microscopy. Chem. Sci. 13, 8605–8617 (2022).
pubmed: 35974762
pmcid: 9337740
doi: 10.1039/D1SC06466E
Harbeson, S. L. et al. Altering metabolic profiles of drugs by precision deuteration 2: discovery of a deuterated analog of ivacaftor with differentiated pharmacokinetics for clinical development. J. Pharmacol. Exp. Ther. 362, 359–367 (2017).
pubmed: 28611092
doi: 10.1124/jpet.117.241497
Looker, A. R. et al. Utilizing O-quinone methide chemistry: synthesis of d
pubmed: 31846324
doi: 10.1021/acs.joc.9b02552
Danese, S. & Peyrin-Biroulet, L. Selective tyrosine kinase 2 inhibition for treatment of inflammatory bowel disease: new hope on the rise. Inflamm. Bowel Dis. 27, 2023–2030 (2021).
pubmed: 34089259
pmcid: 8599029
doi: 10.1093/ibd/izab135
Morand, E. et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 75, 242–252 (2023).
pubmed: 36369798
doi: 10.1002/art.42391
No authors listed. Vertex ramps up CRISPR repair. Nat. Biotechnol. 37, 205 (2019).
doi: 10.1038/s41587-019-0061-y
Dittrich, C. et al. Phase I and pharmacokinetic study of BIBX 1382 BS, an epidermal growth factor receptor (EGFR) inhibitor, given in a continuous daily oral administration. Eur. J. Cancer 38, 1072–1080 (2002).
pubmed: 12008195
doi: 10.1016/S0959-8049(02)00020-5
Diamond, S. et al. Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications. Drug Metab. Dispos. 38, 1277–1285 (2010).
pubmed: 20421447
doi: 10.1124/dmd.110.032375
Zheng, J. et al. Pharmacokinetics and disposition of momelotinib revealed a disproportionate human metabolite—resolution for clinical development. Drug Metab. Dispos. 46, 237 (2018).
pubmed: 29311136
doi: 10.1124/dmd.117.078899
Pryde, D. C. et al. Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J. Med. Chem. 53, 8441–8460 (2010).
pubmed: 20853847
doi: 10.1021/jm100888d
Sharma, R. et al. Deuterium isotope effects on drug pharmacokinetics. I. System-dependent effects of specific deuteration with aldehyde oxidase cleared drugs. Drug Metab. Dispos. 40, 625–634 (2012).
pubmed: 22190693
doi: 10.1124/dmd.111.042770
Kopf, S. et al. Recent developments for the deuterium and tritium labeling of organic molecules. Chem. Rev. 122, 6634–6718 (2022).
pubmed: 35179363
doi: 10.1021/acs.chemrev.1c00795
Treitler, D. S. et al. Development of a commercial process for deucravacitinib, a deuterated API for TYK2 inhibition. Org. Process. Res. Dev. 26, 1202–1222 (2022).
doi: 10.1021/acs.oprd.1c00468
Atzrodt, J., Derdau, V., Fey, T. & Zimmermann, J. The renaissance of H/D exchange. Angew. Chem. Int. Ed. 46, 7744–7765 (2007).
doi: 10.1002/anie.200700039
Atzrodt, J., Derdau, V., Kerr, W. J. & Reid, M. C−H functionalisation for hydrogen isotope exchange. Angew. Chem. Int. Ed. 57, 3022–3047 (2018).
doi: 10.1002/anie.201708903
Prakash, G., Paul, N., Oliver, G. A., Werz, D. B. & Maiti, D. C–H deuteration of organic compounds and potential drug candidates. Chem. Soc. Rev. 51, 3123–3163 (2022).
pubmed: 35320331
doi: 10.1039/D0CS01496F
Rowbotham, J. S., Ramirez, M. A., Lenz, O., Reeve, H. A. & Vincent, K. A. Bringing biocatalytic deuteration into the toolbox of asymmetric isotopic labelling techniques. Nat. Commun. 11, 1454 (2020).
pubmed: 32193396
pmcid: 7081218
doi: 10.1038/s41467-020-15310-z
Loh, Y. Y. et al. Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science 358, 1182–1187 (2017).
pubmed: 29123019
pmcid: 5907472
doi: 10.1126/science.aap9674
Zhou, R., Ma, L., Yang, X. & Cao, J. Recent advances in visible-light photocatalytic deuteration reactions. Org. Chem. Front. 8, 426–444 (2021).
doi: 10.1039/D0QO01299H
Shi, Q. et al. Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions. Nat. Commun. 13, 4453 (2022).
pubmed: 35915119
pmcid: 9343372
doi: 10.1038/s41467-022-32238-8
Norcott, P. L. Current electrochemical approaches to selective deuteration. ChemComm 58, 2944–2953 (2022).
Li, N., Li, Y., Wu, X., Zhu, C. & Xie, J. Radical deuteration. Chem. Soc. Rev. 51, 6291–6306 (2022).
pubmed: 35856093
doi: 10.1039/D1CS00907A
Steverlynck, J., Sitdikov, R. & Rueping, M. The deuterated “Magic Methyl” group: a guide to site-selective trideuteromethyl incorporation and labeling by using CD
pubmed: 34076925
doi: 10.1002/chem.202101179
Sun, Q. & Soulé, J.-F. Broadening of horizons in the synthesis of CD
pubmed: 34605827
doi: 10.1039/D1CS00544H
Wang, L., Xia, Y., Derdau, V. & Studer, A. Remote site-selective radical C(sp
doi: 10.1002/anie.202104254