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説明
Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. Originally, Remdesivir was developed as an injectable solution for the treatment of Ebola virus diseases. Later, the U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) to remdesivir for the treatment of COVID-19. During the COVID-19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID-19 in around 50 countries.
来歴
Remdesivir (trade name: Veklury, developed by Gilead Sciences, Inc.) is a SARS-CoV-2 nucleotide-like RNA polymerase inhibitor, first approved by the FDA for the treatment of COVID-19 on October 22, 2020. By January 21, 2022, Veklury was approved for the treatment of non-hospitalized patients at high risk of COVID-19 disease progression. In April of the same year, it was approved as the first and only treatment for COVID-19 patients under the age of 12. As of August 24, 2023, Veklury was being used to treat COVID-19 in patients with mild to severe hepatic impairment without dose adjustment.
使用
Remdesivir was originally developed to treat hepatitis C,and was subsequently investigated for Ebola virus disease and Marburg virus infections before being studied as a post-infection treatment for COVID-19.
定義
ChEBI: Remdesivir is a carboxylic ester resulting from the formal condensation of the carboxy group of N-[(S)-{[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl]methoxy}(phenoxy)phosphoryl]-L-alanine with the hydroxy group of 2-ethylbutan-1-ol. A broad-spectrum antiviral prodrug with potent in vitro antiviral activity against a diverse panel of RNA viruses such as Ebola virus, MERS-CoV and SARS-CoV. It is currently in Phase III clinical trials for the treatment of Covid-19 in adults. It has a role as an antiviral drug, a prodrug and an anticoronaviral agent. It is a carboxylic ester, a pyrrolotriazine, a nitrile, a phosphoramidate ester, a C-nucleoside and an aromatic amine. It is functionally related to a GS-441524.
適応症
Remdesivir is an antiviral nucleotide analogue used for therapy of severe novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection. Remdesivir therapy is given intravenously for 3 to 10 days and is frequently accompanied by transient, reversible mild-to-moderate elevations in serum aminotransferase levels but has been only rarely linked to instances of clinically apparent liver injury, its hepatic effects being overshadowed by the systemic effects of COVID-19.
副作用
The most common adverse effects in people treated with remdesivir were respiratory failure and blood biomarkers of organ impairment, including low albumin, low potassium, low count of red blood cells, low count of thrombocytes, and elevated bilirubin (jaundice).Other reported adverse effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), infusion site reactions, and electrocardiogram abnormalities. Remdesivir may cause infusion‐related reactions, including low blood pressure, nausea, vomiting, sweating or shivering.
合成
2-Ethylbutyl-L-alanine (47) was reacted with phenylphosphinodic acid dichloride and 4-nitrophenol to generate a mixture of diastereoisomers of the phosphoramidate 48 (Scheme 10). The (S)-P isomer 49 was selectively isolated in 39% yield by diisopropyl ether-induced recrystallization. The iodide 51 was subjected to a metal-halogen exchange reaction and reacted with the ribonolactone 50 to generate the glycosylated product 52 in 40% yield. 52 was reacted with TMSCN (trimethylsilyl cyanide) at low temperature to give the nitrile 53 in 85% yield, and the desired β-isomer was obtained in a >95:5 diastereomeric ratio. The use of trifluoroacetic acid in the reaction was essential to establish high selectivity. A Lewis acid-mediated global benzyl deprotection reaction was used to obtain compound 54 in 86% yield by crystallization. The 2',3'-hydroxyl group of compound 54 was ketal-protected using 2,2-dimethoxypropane to give compound 55. The protection step is crucial for the yield of the subsequent coupling reaction. The protected nucleoside 55 was coupled with the prodrug precursor 49 to give 56 in 70% yield. Acid-mediated deprotection of the ketal compound 56 gave the prodrug remdesivir (VII) in 69% yield.
Mode of action
As an adenosine nucleoside triphosphate analog (GS-443902),the active metabolite of remdesivir interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production.In some viruses, such as the respiratory syncytial virus, it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain.For the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2, arrest of RNA synthesis occurs after incorporation of three additional nucleotides.Hence, remdesivir is classified as a direct-acting antiviral agent that works as a delayed chain terminator.
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