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GS-441524

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GS-441524
Legal status
Legal status
  • US: Investigational drug
Identifiers
  • (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile
CAS Number
PubChem CID
KEGG
ChEMBL
Chemical and physical data
FormulaC12H13N5O4
Molar mass291.26 g·mol−1
3D model (JSmol)
  • C1=C2C(=NC=NN2C(=C1)[C@]3([C@@H]([C@@H]([C@H](O3)CO)O)O)C#N)N
  • InChI=1S/C12H13N5O4/c13-4-12(10(20)9(19)7(3-18)21-12)8-2-1-6-11(14)15-5-16-17(6)8/h1-2,5,7,9-10,18-20H,3H2,(H2,14,15,16)/t7-,9-,10-,12+/m1/s1
  • Key:BRDWIEOJOWJCLU-LTGWCKQJSA-N

GS-441524 is an antiviral drug which was developed by Gilead Sciences. It is the main plasma metabolite of the antiviral prodrug remdesivir, which has a half-life of around 24 hours in human patients. GS-441524 nucleoside is phosphorylated by nucleoside kinases (probably adenosine kinase (ADK), which is the enzyme that phosphorylates the structurally similar ribavirin), and then phosphorylated again by nucleoside-diphosphate kinase (NDK) to the active nucleotide triphosphate form. Remdesivir and GS-441524 were both tested against feline infectious peritonitis (FIP) in cell culture and found to be equivalent. Remdesivir was never tested in cats but GS-441524 has been found to be effective treatment for FIP, a lethal coronavirus disease which affects domestic cats and is widely used despite no official FDA approval due to Gilead's refusal to license this drug for veterinary use.[1][2][3][4] GS-441524 is either similar to or more potent than remdesivir against SARS-CoV-2 in cell culture,[5] with some researchers arguing that GS-441524 would be better than remdesivir for the treatment of COVID-19.[6][7][8][9] Specific advantages cited include ease of synthesis, lower hepatotoxicity, and potential for oral delivery (which is precluded of remdesivir because of poor hepatic stability and first pass metabolism).[citation needed]

Use

Since FIP is usually fatal and there are no approved treatments available, GS-441524 has reportedly been sold on the black market and used by pet owners to treat affected cats, although Gilead Sciences has refused to license the drug for veterinary use. Its efficacy for this purpose has been conclusively demonstrated in multiple trials, including field trials.[10][11][12]

GS-441524 is the nucleoside of the prodrug remdesivir. It is remdesivir's predominant metabolite circulating in the serum due to rapid hydrolysis followed by dephosphorylation.[13][14][15] Some researchers have suggested its utility as a treatment for COVID-19 and pointed out advantages over Remdesivir, including lack of on-target liver toxicity and much cheaper and simpler synthesis.[16][17]

See also

References

  1. ^ https://www.vettimes.co.uk/news/vet-science-being-ignored-in-quest-for-covid-19-drug/
  2. ^ https://www.theatlantic.com/science/archive/2020/05/remdesivir-cats/611341/
  3. ^ Murphy, B.G.; Perron, M.; Murakami, E.; Bauer, K.; Park, Y.; Eckstrand, C.; Liepnieks, M.; Pedersen, N.C. (2018). "The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies". Veterinary Microbiology. 219: 226–233. doi:10.1016/j.vetmic.2018.04.026. PMC 7117434. PMID 29778200.
  4. ^ Pedersen, Niels C; Perron, Michel; Bannasch, Michael; Montgomery, Elizabeth; Murakami, Eisuke; Liepnieks, Molly; Liu, Hongwei (2019). "Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis". Journal of Feline Medicine and Surgery. 21 (4): 271–281. doi:10.1177/1098612X19825701. PMC 6435921. PMID 30755068.
  5. ^ https://www.biorxiv.org/content/10.1101/2020.04.27.064279v1
  6. ^ Yan V, Muller F (2020). "Advantages of the parent nucleoside GS-441524 over remdesivir for Covid-19 treatment". ACS Medicinal Chemistry Letters. doi:10.1021/acsmedchemlett.0c00316. S2CID 220056568.
  7. ^ Yan VC, Muller FL (14 May 2020). "Gilead should ditch remdesivir and focus on its simpler and safer ancestor". Statnews.
  8. ^ https://www.pharmazeutische-zeitung.de/remdesivir-metabolit-noch-schaerfere-waffe-gegen-covid-19-117613/
  9. ^ https://www.vettimes.co.uk/news/vet-science-being-ignored-in-quest-for-covid-19-drug/
  10. ^ https://www.vettimes.co.uk/news/vet-science-being-ignored-in-quest-for-covid-19-drug/
  11. ^ https://www.theatlantic.com/science/archive/2020/05/remdesivir-cats/611341/
  12. ^ Burns K (15 January 2020). "FIP drugs continue to show promise, while being sold on black market". Journal of the American Veterinary Medical Association News.
  13. ^ Warren, Travis K.; Jordan, Robert; Lo, Michael K.; Ray, Adrian S.; Mackman, Richard L.; Soloveva, Veronica; Siegel, Dustin; Perron, Michel; Bannister, Roy; Hui, Hon C.; Larson, Nate; Strickley, Robert; Wells, Jay; Stuthman, Kelly S.; Van Tongeren, Sean A.; Garza, Nicole L.; Donnelly, Ginger; Shurtleff, Amy C.; Retterer, Cary J.; Gharaibeh, Dima; Zamani, Rouzbeh; Kenny, Tara; Eaton, Brett P.; Grimes, Elizabeth; Welch, Lisa S.; Gomba, Laura; Wilhelmsen, Catherine L.; Nichols, Donald K.; Nuss, Jonathan E.; Nagle, Elyse R.; Kugelman, Jeffrey R.; Palacios, Gustavo; Doerffler, Edward; Neville, Sean; Carra, Ernest; Clarke, Michael O.; Zhang, Lijun; Lew, Willard; Ross, Bruce; Wang, Queenie; Chun, Kwon; Wolfe, Lydia; Babusis, Darius; Park, Yeojin; Stray, Kirsten M.; Trancheva, Iva; Feng, Joy Y.; Barauskas, Ona; Xu, Yili; Wong, Pamela; Braun, Molly R.; Flint, Mike; McMullan, Laura K.; Chen, Shan-Shan; Fearns, Rachel; Swaminathan, Swami; Mayers, Douglas L.; Spiropoulou, Christina F.; Lee, William A.; Nichol, Stuart T.; Cihlar, Tomas; Bavari, Sina (March 2016). "Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys". Nature. 531 (7594): 381–385. doi:10.1038/nature17180. PMC 5551389. PMID 26934220.
  14. ^ Sheahan, Timothy P.; Sims, Amy C.; Graham, Rachel L.; Menachery, Vineet D.; Gralinski, Lisa E.; Case, James B.; Leist, Sarah R.; Pyrc, Krzysztof; Feng, Joy Y.; Trantcheva, Iva; Bannister, Roy; Park, Yeojin; Babusis, Darius; Clarke, Michael O.; Mackman, Richard L.; Spahn, Jamie E.; Palmiotti, Christopher A.; Siegel, Dustin; Ray, Adrian S.; Cihlar, Tomas; Jordan, Robert; Denison, Mark R.; Baric, Ralph S. (28 June 2017). "Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses". Science Translational Medicine. 9 (396): eaal3653. doi:10.1126/scitranslmed.aal3653. PMC 5567817. PMID 28659436.
  15. ^ Williamson, Brandi N.; Feldmann, Friederike; Schwarz, Benjamin; Meade-White, Kimberly; Porter, Danielle P.; Schulz, Jonathan; Doremalen, Neeltje van; Leighton, Ian; Yinda, Claude Kwe; Pérez-Pérez, Lizzette; Okumura, Atsushi; Lovaglio, Jamie; Hanley, Patrick W.; Saturday, Greg; Bosio, Catharine M.; Anzick, Sarah; Barbian, Kent; Cihlar, Tomas; Martens, Craig; Scott, Dana P.; Munster, Vincent J.; Wit, Emmie de (22 April 2020). "Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2". bioRxiv: 2020.04.15.043166. doi:10.1101/2020.04.15.043166.
  16. ^ Yan, Victoria C; Muller, Florian L "Gilead should ditch remdesivir and focus on its simpler ancestor". STAT. 14 May 2020.
  17. ^ Yan, Victoria C and Muller; Florian L. Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment. (2020) ACS Medicinal Chemistry Letters. https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00316
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