Remdesivir

Cat. No.: B604916

CAS No.: 1809249-37-3

M. Wt: 602.6 g/mol

InChI Key: RWWYLEGWBNMMLJ-YSOARWBDSA-N

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Overview

1. Description

7. Preparation methods

2. Scientific research applications

8. Chemical reactions analysis

3. Mechanism of action

9. Comparison with similar compounds

4. Safety and hazards

10. Properties

5. Future directions

11. Disclaimer

6. Biochemical analysis

Description

It was initially developed by Gilead Sciences for the treatment of Ebola virus disease and has since gained significant attention for its potential use against other viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19 .

Scientific Research Applications

GS-5734 has a wide range of scientific research applications, including:

Chemistry: Used as a model compound for studying nucleoside analogs and their reactions.

Biology: Investigated for its antiviral activity against a variety of RNA viruses.

Medicine: Approved for the treatment of COVID-19 and studied for its potential use against other viral infections such as Ebola, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS)

Industry: Used in the development of antiviral therapies and as a reference compound in pharmaceutical research

Mechanism of Action

Safety and Hazards

Remdesivir can cause gastrointestinal symptoms (e.g., nausea), elevated transaminase levels, an increase in prothrombin time without a change in the international normalized ratio, and hypersensitivity reactions. Bradycardia has also been reported.

Future Directions

Remdesivir has been studied in several clinical trials for the treatment of COVID-19. The recommendations from the COVID-19 Treatment Guidelines Panel are based on the results of these studies. It is crucial to continue these studies to improve COVID-19 treatment in the future.

Biochemical Analysis

Biochemical Properties

Remdesivir interacts with the viral RNA-dependent RNA polymerase, an enzyme crucial for viral replication . It is metabolized by the host cell into its active form, a triphosphate (TP) metabolite . This metabolite inhibits viral replication by acting as a chain terminator during the synthesis of viral RNA .

Cellular Effects

This compound has been shown to inhibit the replication of various coronaviruses in human airway epithelial cells . It reduces viral load and improves clinical signs of disease as well as respiratory function .

Molecular Mechanism

The active triphosphate metabolite of this compound incorporates into the growing RNA chain during viral replication. This causes premature termination of the RNA synthesis, thereby inhibiting the replication of the virus . It’s worth noting that this compound can exert its effects even in the presence of the viral proofreading exoribonuclease, an enzyme that often complicates the development of antiviral nucleosides .

Temporal Effects in Laboratory Settings

In laboratory settings, this compound has shown to reduce viral RNA levels in a dose-dependent manner that parallels impairment of viral titer . While it is highly active against wild-type viruses, it has been found to be even more active against viruses lacking the proofreading activity of the exoribonuclease .

Dosage Effects in Animal Models

In animal models, both prophylactic and early therapeutic administration of this compound have significantly reduced lung viral load and improved clinical signs of disease . A study on male mice suggested that a high dosage of this compound may induce testicular toxicity and result in deterioration of sperm parameters .

Metabolic Pathways

This compound is a prodrug that requires metabolism by the host cell to form the pharmacologically active triphosphate metabolite

Transport and Distribution

As a prodrug, it is designed to deliver the nucleoside monophosphate into the cell, thereby circumventing the rate-limiting first phosphorylation step and allowing for efficient intracellular delivery .

Preparation Methods

Synthetic Routes and Reaction Conditions

The synthesis of GS-5734 involves multiple steps, starting from commercially available starting materials. The key steps include the formation of the nucleoside analog and its subsequent phosphorylation to produce the active triphosphate form. The synthetic route typically involves protection and deprotection steps, nucleophilic substitution reactions, and phosphorylation reactions under controlled conditions .

Industrial Production Methods

Industrial production of GS-5734 follows a similar synthetic route but is optimized for large-scale manufacturing. This involves the use of high-yielding reactions, efficient purification methods, and stringent quality control measures to ensure the consistency and purity of the final product .

Chemical Reactions Analysis

Types of Reactions

GS-5734 undergoes several types of chemical reactions, including:

Oxidation: GS-5734 can be oxidized to form various metabolites.

Reduction: Reduction reactions can modify the nucleoside analog structure.

Substitution: Nucleophilic substitution reactions are involved in the synthesis of GS-5734

Common Reagents and Conditions

Common reagents used in the synthesis and reactions of GS-5734 include:

Phosphorylating agents: Used for the phosphorylation steps.

Protecting groups: Used to protect functional groups during synthesis.

Solvents: Such as dimethyl sulfoxide (DMSO) and acetonitrile, used as reaction media.

Major Products Formed

The major products formed from the reactions of GS-5734 include its active triphosphate form, remdesivir triphosphate, and various metabolites formed through oxidation and reduction reactions .

Comparison with Similar Compounds

Similar Compounds

GS-441524: A parent nucleoside analog of GS-5734 with similar antiviral activity.

Favipiravir: Another nucleoside analog with broad-spectrum antiviral activity.

Ribavirin: A nucleoside analog used to treat various viral infections.

Uniqueness of GS-5734

GS-5734 is unique due to its broad-spectrum antiviral activity and its ability to inhibit a wide range of RNA viruses, including coronaviruses and filoviruses. Its efficacy against SARS-CoV-2 has made it a critical component in the fight against COVID-19 .

Properties

IUPAC Name	2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI	InChI=1S/C27H35N6O8P/c1-4-18(5-2)13-38-26(36)17(3)32-42(37,41-19-9-7-6-8-10-19)39-14-21-23(34)24(35)27(15-28,40-21)22-12-11-20-25(29)30-16-31-33(20)22/h6-12,16-18,21,23-24,34-35H,4-5,13-14H2,1-3H3,(H,32,37)(H2,29,30,31)/t17-,21+,23+,24+,27-,42-/m0/s1	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI Key	RWWYLEGWBNMMLJ-YSOARWBDSA-N	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Canonical SMILES	CCC(CC)COC(=O)C(C)NP(=O)(OCC1C(C(C(O1)(C#N)C2=CC=C3N2N=CN=C3N)O)O)OC4=CC=CC=C4	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Isomeric SMILES	CCC(CC)COC(=O)[C@H](C)N[P@](=O)(OC[C@@H]1[C@H]([C@H]([C@](O1)(C#N)C2=CC=C3N2N=CN=C3N)O)O)OC4=CC=CC=C4	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Formula	C27H35N6O8P	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

DSSTOX Substance ID	DTXSID701022537	Source
Record name	Remdesivir
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID701022537
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight	602.6 g/mol	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Mechanism of Action	COVID-19 is caused by the positive-sense RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of the viral genome is a key step in the infectious cycle of RNA viruses, including those of the _Filoviridae_, _Paramyxoviridae_, _Pneumoviridae_, and _Coronaviridae_ families, and is carried out by viral RNA-dependent RNA polymerase (RdRp) enzymes or enzyme complexes. For both SARS-CoV and SARS-CoV-2, the RdRp comprises nsp7, nsp8, and nsp12 subunits under physiological conditions, although functional RdRp complexes can be reassembled _in vitro_ that incorporate only the nsp8 and nsp12 subunits, similar to the Middle East respiratory syndrome coronavirus (MERS-CoV). Remdesivir is a phosphoramidite prodrug of a 1'-cyano-substituted adenosine nucleotide analogue that competes with ATP for incorporation into newly synthesized viral RNA by the corresponding RdRp complex. Remdesivir enters cells before being cleaved to its monophosphate form through the action of either carboxylesterase 1 or cathepsin A; it is subsequently phosphorylated by undescribed kinases to yield its active triphosphate form remdesivir triphosphate (RDV-TP or GS-443902). RDV-TP is efficiently incorporated by the SARS-CoV-2 RdRp complex, with a 3.65-fold selectivity for RDV-TP over endogenous ATP. Unlike some nucleoside analogues, remdesivir provides a free 3'-hydroxyl group that allows for continued chain elongation. However, modelling and _in vitro_ experiments suggest that at _i_ + 4 (corresponding to the position for the incorporation of the fourth nucleotide following RDV-TP incorporation), the 1'-cyano group of remdesivir sterically clashes with Ser-861 of the RdRp, preventing further enzyme translocation and terminating replication at position _i_ + 3. This mechanism was essentially identical between SARS-CoV, SARS-CoV-2, and MERS-CoV, and genomic comparisons reveal that Ser-861 is conserved across alpha-, beta-, and deltacoronaviruses, suggesting remdesivir may possess broad antiviral activity. Considerations for the use of nucleotide analogues like remdesivir include the possible accumulation of resistance mutations. Excision of analogues through the 3'-5' exonuclease (ExoN) activity of replication complexes, mediated in SARS-CoV by the nsp14 subunit, is of possible concern. Murine hepatitis viruses (MHVs) engineered to lack ExoN activity are approximately 4-fold more susceptible to remdesivir, supporting the proposed mechanism of action. However, the relatively mild benefit of ExoN activity to remdesivir resistance is proposed to involve its delayed chain termination mechanism, whereby additional endogenous nucleotides are incorporated following RDV-TP. In addition, serial passage of MHV in increasing concentrations of the remdesivir parent molecule [GS-441524] led to the development of resistance mutations F476L and V553L, which maintain activity when transferred to SARS-CoV. However, these mutant viruses are less fit than wild-type in both competition assays and _in vivo_ in the absence of selective pressure. To date, no clinical data on SARS-CoV-2 resistance to remdesivir have been described.	Source
Record name	Remdesivir
Source	DrugBank
URL	https://www.drugbank.ca/drugs/DB14761
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CAS No.	1809249-37-3	Source
Record name	L-Alanine, N-[(S)-hydroxyphenoxyphosphinyl]-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-D-altrononitrile
Source	CAS Common Chemistry
URL	https://commonchemistry.cas.org/detail?cas_rn=1809249-37-3
Description	CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society.
Explanation	The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.

Record name	Remdesivir [USAN]
Source	ChemIDplus
URL	https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=1809249373
Description	ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system.

Record name	Remdesivir
Source	DrugBank
URL	https://www.drugbank.ca/drugs/DB14761
Description	The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation	Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)

Record name	Remdesivir
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID701022537
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Record name	2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
Source	European Chemicals Agency (ECHA)
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Record name	REMDESIVIR
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