Synthesis and anti-SARS-CoV-2 activity of deuterated GS-441524 analogs

Zheng, Wei; Hu, Tianwen; Wei, Daibao; Xie, Yuanchao; Shen, Jingshan

doi:10.1016/j.tetlet.2022.154012

Cited by 6 publications

(2 citation statements)

References 15 publications

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“…Deuterated GS-441524 derivatives provide a beneficial strategy for the development and selection of oral antiviral drugs. Deuteration has gained overwhelming popularity ( 120 ). However, owing to synthetic difficulties, only 7-deuterated derivatives of GS-441524 (pyrrolotriazine moiety) have been obtained.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Wang

Yang

Song³

2022

Front. Immunol.

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GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Wang

Yang

Song³

2022

Front. Immunol.

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“…In a subsequent study, 40 Zheng et al describe a more efficient approach to the synthesis of 19 which involves reducing 18 with triethylamine, palladium, and deuterium gas (D 2 ) at 60 °C for 1 h. In this method, 19 was produced in 92% yield with D incorporation of 99%. In addition, Zheng and co-workers reported the synthesis of deuterated analogues of GS-441524 ( 20 and 20a – d ) along with a comparison of their efficacy against SARS-CoV-2 in vitro against nondeuterated GS-441524 ( 16 ) ( Table 1 ).…”

Section: Deuterated Drugs As Therapeutics For the Treatment Of Covid-19mentioning

confidence: 99%

Deuterated Drugs and Biomarkers in the COVID-19 Pandemic

et al. 2022

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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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Is it still worth renewing nucleoside anticancer drugs nowadays?

Liu

2024

European Journal of Medicinal Chemistry

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Synthesis and anti-SARS-CoV-2 activity of deuterated GS-441524 analogs

Cited by 6 publications

References 15 publications

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Deuterated Drugs and Biomarkers in the COVID-19 Pandemic

Is it still worth renewing nucleoside anticancer drugs nowadays?

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