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Review
. 2022 Nov 13;7(46):41840-41858.
doi: 10.1021/acsomega.2c04160. eCollection 2022 Nov 22.

Deuterated Drugs and Biomarkers in the COVID-19 Pandemic

Ross D Jansen-van Vuuren  1   2 , Luka Jedlovčnik  1 , Janez Košmrlj  1 , Thomas E Massey  3 , Volker Derdau  4
Affiliations
Review

Deuterated Drugs and Biomarkers in the COVID-19 Pandemic

Ross D Jansen-van Vuuren et al. ACS Omega. .

Abstract

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially identified in Wuhan (China) in December 2019, COVID-19 rapidly spread globally, resulting in the COVID-19 pandemic. Carriers of the SARS-CoV-2 can experience symptoms ranging from mild to severe (or no symptoms whatsoever). Although vaccination provides extra immunity toward SARS-CoV-2, there has been an urgent need to develop treatments for COVID-19 to alleviate symptoms for carriers of the disease. In seeking a potential treatment, deuterated compounds have played a critical role either as therapeutic agents or as internal MS standards for studying the pharmacological properties of new drugs by quantifying the parent compounds and metabolites. We have identified >70 examples of deuterium-labeled compounds associated with treatment of COVID-19. Of these, we found 9 repurposed drugs and >20 novel drugs studied for potential therapeutic roles along with a total of 38 compounds (drugs, biomarkers, and lipids) explored as internal mass spectrometry standards. This review details the synthetic pathways and modes of action of these compounds (if known), and a brief analysis of each study.

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Conflict of interest statement

The authors declare the following competing financial interest(s): V.D. is an employee of Sanofi and may hold shares or options in the company. The other authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Three main advantages potentially provided by deuterated drugs: increased (A) safety, (B) tolerability, and (C) bioavailability. These are achieved, respectively, by (A) “metabolic shunting”, resulting in reduced exposure to undesirable (toxic or reactive) metabolites, (B) reduced systemic clearance, resulting in increased half-life, and (C) first-pass metabolism, resulting in higher bioavailability of the nonmetabolized drug. AUC is area under the curve and represents drug exposure over time; Cmax is the maximum or peak concentration of a drug. Adapted with permission from ref (24). Copyright 2014 The Pharmaceutical Society of Japan.
Figure 2
Figure 2
Chemical structures of deutetrabenazine (1), tetrabenazine (2), deupirfenidone (3), and pirfenidone (4). Also shown are compound 5, the primary metabolite of both 3 and 4, and compounds 6 and 7, the secondary metabolites of 3.
Scheme 1
Scheme 1. Suzuki-Coupling Approaches to the Synthesis of Deupirfenidone (3): (a) Methylation-Last Route and (b) Methylation-First Route
Figure 3
Figure 3
Chemical structures of RdRp inhibitors 12–16.
Scheme 2
Scheme 2. Synthetic Pathway to VV116 (15) Commencing with Nondeuterated Substrate 17
Adapted with permission from ref (38). Copyright 2021 Springer Nature.
Scheme 3
Scheme 3. (a) Chemical Structures of ACH-3422 (22) and the Parent Drug PSI-7851 (23); (b) Synthesis of ACH-3422 by Initial Preparation of Deuterated Acetonide 26 Followed by a Double OH Deprotection to 27, which Then Reacts with 28 To Form the Deuterated Thymine Analogue 22
Scheme 4
Scheme 4. Metabolic Profile of Dexamethasone (29)
Scheme 5
Scheme 5. (a) Generation of DCl from Reaction of Prenyl Chloride 32 with Methanol-d4 Followed by (b) Acid-Catalyzed H/D Exchange of Dexamethasone (29) at C-6
(a) Adapted with permission from ref (49). Copyright 2021 Royal Society of Chemistry.
Scheme 6
Scheme 6. (a) Hydrogen Abstraction of a Bisallylic Hydrogen, Where the Key Step of PUFA Oxidation Is Inhibited by Deuteration; (b) Synthesis of the Ethyl Ester of Arachidonic Acid-d6 (35) from the Nondeuterated Analogue (34)
Adapted with permission from ref (51). Copyright 2022 MDPI.
Figure 4
Figure 4
Chemical structure of 3CLpro inhibitor GC376 (36). P1, P2 and P3 are the fragments of the inhibitor known to bind to the active site of Mpro (the protease that is key to the replication of SARS-CoV-2).
Scheme 7
Scheme 7. Synthesis of Deuterated GC376 Derivatives 39–40 As Described by Dampalla et al.,
Figure 5
Figure 5
Chemical structures of deuterated alcohol substrates 37d–m used in the synthesis of GC376 derivatives 39 and 40.
Figure 6
Figure 6
Chemical structures of azetidine-containing inhibitors 39d and 40i.
Scheme 8
Scheme 8. Generic Schematic Showing Preparation of Deuterated Alcohols (37i–l) from Commercially Available Carboxylic Acid Precursors
Scheme 9
Scheme 9. (a) General Chemical Structure of Mpro Inhibitor 41 Explored by Quan et al.; (b) Reaction To Form General Deuterated Mpro Inhibitor, 42: (i) Formyl-Selective Deuteration of Nicotinaldeyde to 43, (ii) Classical One-Pot Ugi-4CR To Form Diamine Derivative 44, and (iii) Dess–Martin Oxidation of 44 to 42; (c) Chemical Structures of 45 (Y180) and Its Nondeuterated Analogue 46
Figure 7
Figure 7
Chemical structures of internal MS standards 47–51.
Figure 8
Figure 8
Chemical structures of internal MS standards 52–56.
Figure 9
Figure 9
Chemical structures of ebselen (58) and its analogue (major metabolite of BS1801) 57, along with 59 (M2) and its deuterated analogue 60 (M2-d6).
Scheme 10
Scheme 10. Synthesis of 60 from 57 via Grignard Chemistry
Adapted with permission from ref (73). Copyright 2022 Elsevier.
Figure 10
Figure 10
Chemical structures of baricitinib-d5 (61) and nondeuterated baricitinib (62).
Scheme 11
Scheme 11. Synthesis of Deuterated Baricitinib (61) in a 29% Overall Yield, Starting from Commercially Available Ethanethiol-d5
Adapted with permission from ref (76). Copyright 2022 John Wiley & Sons, Inc.
Scheme 12
Scheme 12. Synthesis of Deuterated Dissacharide 67
Reagents and conditions: (a) (i) 5 M NaOH/MeOH/CHCl3/H2O, rt, 48 h; (ii) n-BuI-d9, KHCO3, DMF, rt, 24 h; (b) 20% Pd(OH)2/C, MeOH, rt, 24 h. Adapted with permission from ref (79). Copyright 2019 American Chemical Society.
Figure 11
Figure 11
Chemical structures of commercially available deuterium-labeled lipids and lipid mediators 70–74.
See this image and copyright information in PMC

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