WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 555299
CAS#: 1191237-69-0 (free base)
Description: GS-441524 is a potent inhibitor of feline infectious peritonitis (FIP) virus with an EC50 of 0.78 μM.. GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. Note: GS-441524 is an active metabolite of Remdesivir.
MedKoo Cat#: 555299
CAS#: 1191237-69-0 (free base)
Chemical Formula: C12H13N5O4
Exact Mass: 291.0968
Molecular Weight: 291.1
Elemental Analysis: C, 49.48; H, 4.50; N, 24.04; O, 21.97
Synonym: GS-441524; GS 441524; GS441524; Remdesivir-metabolite, GS-5734-metabolite; GS5734-metabolite; GS 5734-metabolite;
IUPAC/Chemical Name: (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile
InChi Key: BRDWIEOJOWJCLU-LTGWCKQJSA-N
InChi Code: 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
SMILES Code: N#C[C@@]1(C2=CC=C3C(N)=NC=NN32)O[C@H](CO)[C@@H](O)[C@H]1O
Appearance: Solid powder
Purity: >97% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||GS-441524, predominant metabolite of Remdesivir and superior to Remdesivir against Covid-19 , shows comparable efficacy in cell-based models of primary human lung and cat cells infected with coronavirus.|
|In vitro activity:||CRFK cells were treated with 100, 33.3, 11.1, 3.7 or 1.2 uM GS-441524 for 24 h. The cells appeared and grew normally at all concentrations of GS-441524 and failed to uptake the fluorescent dye CellTox Green at 24 h (data not shown). The cytotoxic concentration-50% (CC50) was therefore >100 uM. No cytotoxicity (CPE) was observed with CRFK cells exposed to 10 uM of GS-441524 for a longer period of 72 h, either visually or by quantitation of crystal violet staining. It was crucial to show that GS-441524 inhibited FIPV replication in cultured cells at a very low concentration. This was done initially by infecting CRFK cell monolayers with serotype II FIPV-79-1146 and then treating with GS-441524 at concentrations ranging from none to 3.0 uM one hour later. The CRFK cells were protected from virus-induced CPE in a dose-dependent manner when tested 72 h later by crystal violet staining (Fig. 1B). This experiment was repeated three times with similar results and the effective concentration-50% (EC50) of GS-441524 was calculated to be 0.78 uM (Fig. 1C). Inhibition of FIPV replication by GS-441524 was also measured by qRT-RCR in CRFK cells infected with FIPV-79-1146 and exposed one hour later to 50, 10, 1.0, 0.1 and 0 uM GS-441524 for 20 h (Fig. 2 A). Complete inhibition of viral RNA expression was seen at 50 and 10 uM, partial inhibition at 1.0 uM, and no inhibition at lower concentrations (p < 0.0001) (Fig. 2A). Reference: Vet Microbiol. 2018 Jun;219:226-233. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29778200/|
|In vivo activity:||Twelve adolescent laboratory cats were challenge-exposed to this FIPV and their response to GS-441524 treatment monitored when terminal disease signs became apparent. Ten of 12 of these cats, 16–113, 16-116, 16-119, 16-123 and 124, 16-127 to 131, demonstrated clinical signs consistent with FIP within 10-18 days, while two cats (16-115 and 16-118) remained healthy (Fig. 3 ). Clinical signs of FIP in the affected cats started with hyperthermia (>103 F) (Fig. 4 ) and lymphopenia (less than or equal to 1700 cells/ul blood) (Fig. 5 ), and then rapidly progressed to depression, anorexia, hyperbilirubinemia, and ascites. The severity of lymphopenia appeared to be proportional to the severity of overall disease signs and one cat (16–113) had a measured nadir of 143 lymphocytes/ul blood (Fig. 5). Rectal temperature and lymphocyte levels remained normal in the two asymptomatic cats. The 10 cats that developed disease signs were divided into two groups and treated with either 5 mg/kg (Group A; n = 5) or 2 mg/kg (Group B; n = 5) GS-441524 SC q24 h starting three days after unequivocal clinical evidence of FIP (days 12–19 post infection) (Fig. 3, Fig. 4, Fig. 5). The two cats that did not develop disease signs served as controls for normal blood lymphocyte counts and rectal temperature. All 10 treated cats had a rapid response to treatment and lymphocyte levels and rectal temperatures returned to pre-infection levels and levels of the two asymptomatic cats (Figs. 4,5). Two of the 10 treated cats, 16–116 (Group A) and 16–127 (Group B), had recurrences disease at four and six weeks post treatment (Fig. 3). These two cats were treated a second time for two weeks and their response was identical to that of primary treatment (data not shown). All ten of the once or twice treated cats have remained normal to date (more than eight months post infection). No significant signs of toxicity were noted during or after primary or secondary treatment. Injections caused a transient "stinging" reaction in some cats within 10 s of compound administration. Localized and transient pain was evidenced by unusual posturing, licking at the injection site and/or vocalizations that lasted for approximately 30–60 s after injection. Injection reactions were more pronounced in some animals relative to others and reactions were inconsistent from one injection to the next and decreased over time. Reference: Vet Microbiol. 2018 Jun;219:226-233. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29778200/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 291.1 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, Liepnieks M, Pedersen NC. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet Microbiol. 2018 Jun;219:226-233. doi: 10.1016/j.vetmic.2018.04.026. Epub 2018 Apr 22. PMID: 29778200; PMCID: PMC7117434. 2. Huang Z, Gong L, Zheng Z, Gao Q, Chen X, Chen Y, Chen X, Xu R, Zheng J, Xu Z, Zhang S, Wang H, Zhang G. GS-441524 inhibits African swine fever virus infection in vitro. Antiviral Res. 2021 May 1;191:105081. doi: 10.1016/j.antiviral.2021.105081. Epub ahead of print. PMID: 33945807.|
|In vivo protocol:||1. Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, Liepnieks M, Pedersen NC. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet Microbiol. 2018 Jun;219:226-233. doi: 10.1016/j.vetmic.2018.04.026. Epub 2018 Apr 22. PMID: 29778200; PMCID: PMC7117434. 2. Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 2019 Apr;21(4):271-281. doi: 10.1177/1098612X19825701. Epub 2019 Feb 13. PMID: 30755068; PMCID: PMC6435921.|
1: Shafer RW. A SARS-CoV-2 antiviral therapy score card. Glob Health Med. 2020 Dec 31;2(6):346-349. doi: 10.35772/ghm.2020.01082. PMID: 33409413; PMCID: PMC7780285.
2: Hanafin PO, Jermain B, Hickey AJ, Kabanov AV, Kashuba AD, Sheahan TP, Rao GG. A Mechanism-based Pharmacokinetic Model of Remdesivir Leveraging Interspecies Scaling to Simulate COVID-19 Treatment in Humans. CPT Pharmacometrics Syst Pharmacol. 2020 Dec 9. doi: 10.1002/psp4.12584. Epub ahead of print. PMID: 33296558.
3: Nili A, Farbod A, Neishabouri A, Mozafarihashjin M, Tavakolpour S, Mahmoudi H. Remdesivir: A beacon of hope from Ebola virus disease to COVID-19. Rev Med Virol. 2020 Nov;30(6):1-13. doi: 10.1002/rmv.2133. Epub 2020 Jul 30. PMID: 33210457.
4: Dickinson PJ. Coronavirus Infection of the Central Nervous System: Animal Models in the Time of COVID-19. Front Vet Sci. 2020 Oct 23;7:584673. doi: 10.3389/fvets.2020.584673. PMID: 33195610; PMCID: PMC7644464.
5: Jung LS, Gund TM, Narayan M. Comparison of Binding Site of Remdesivir and Its Metabolites with NSP12-NSP7-NSP8, and NSP3 of SARS CoV-2 Virus and Alternative Potential Drugs for COVID-19 Treatment. Protein J. 2020 Dec;39(6):619-630. doi: 10.1007/s10930-020-09942-9. Epub 2020 Nov 13. PMID: 33185784; PMCID: PMC7662030.
6: Davis MR, Pham CU, Cies JJ. Remdesivir and GS-441524 plasma concentrations in patients with end-stage renal disease on haemodialysis. J Antimicrob Chemother. 2020 Nov 5:dkaa472. doi: 10.1093/jac/dkaa472. Epub ahead of print. PMID: 33152758.
7: Izes AM, Yu J, Norris JM, Govendir M. Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats. Vet Q. 2020 Dec;40(1):322-330. doi: 10.1080/01652176.2020.1845917. PMID: 33138721; PMCID: PMC7671703.
8: Sahakijpijarn S, Moon C, Koleng JJ, Christensen DJ, Williams Iii RO. Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing. Pharmaceutics. 2020 Oct 22;12(11):1002. doi: 10.3390/pharmaceutics12111002. PMID: 33105618; PMCID: PMC7690377.
9: Yan VC, Muller FL. Captisol and GS-704277, but Not GS-441524, Are Credible Mediators of Remdesivir's Nephrotoxicity. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01920-20. doi: 10.1128/AAC.01920-20. PMID: 32988821; PMCID: PMC7674034.
10: Lê MP, Le Beller C, Le Hingrat Q, Jaquet P, Wicky PH, Bunel V, Massias L, Visseaux B, Messika J, Descamps D, Mal H, Timsit JF, Peytavin G. Reply to Yan and Muller, "Captisol and GS-704277, but Not GS-441524, Are Credible Mediators of Remdesivir's Nephrotoxicity". Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01937-20. doi: 10.1128/AAC.01937-20. PMID: 32988815; PMCID: PMC7674048.
11: Paltrinieri S, Giordano A, Stranieri A, Lauzi S. Feline infectious peritonitis (FIP) and coronavirus disease 19 (COVID-19): Are they similar? Transbound Emerg Dis. 2020 Sep 28:10.1111/tbed.13856. doi: 10.1111/tbed.13856. Epub ahead of print. PMID: 32985113; PMCID: PMC7537058.
12: Schooley RT, Carlin AF, Beadle JR, Valiaeva N, Zhang XQ, Garretson AF, Smith VI, Murphy J, Hostetler KY. Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity. bioRxiv [Preprint]. 2020 Aug 27:2020.08.26.269159. doi: 10.1101/2020.08.26.269159. PMID: 32869033; PMCID: PMC7457622.
13: Lê MP, Le Hingrat Q, Jaquet P, Wicky PH, Bunel V, Massias L, Visseaux B, Messika J, Descamps D, Mal H, Timsit JF, Peytavin G. Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19. Antimicrob Agents Chemother. 2020 Oct 20;64(11):e01521-20. doi: 10.1128/AAC.01521-20. PMID: 32868327; PMCID: PMC7577145.
14: Pruijssers AJ, George AS, Schäfer A, Leist SR, Gralinksi LE, Dinnon KH 3rd, Yount BL, Agostini ML, Stevens LJ, Chappell JD, Lu X, Hughes TM, Gully K, Martinez DR, Brown AJ, Graham RL, Perry JK, Du Pont V, Pitts J, Ma B, Babusis D, Murakami E, Feng JY, Bilello JP, Porter DP, Cihlar T, Baric RS, Denison MR, Sheahan TP. Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. Cell Rep. 2020 Jul 21;32(3):107940. doi: 10.1016/j.celrep.2020.107940. Epub 2020 Jul 7. PMID: 32668216; PMCID: PMC7340027.
15: Yan VC, Muller FL. Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment. ACS Med Chem Lett. 2020 Jun 23;11(7):1361-1366. doi: 10.1021/acsmedchemlett.0c00316. PMID: 32665809; PMCID: PMC7315846.
16: Tempestilli M, Caputi P, Avataneo V, Notari S, Forini O, Scorzolini L, Marchioni L, Ascoli Bartoli T, Castilletti C, Lalle E, Capobianchi MR, Nicastri E, D'Avolio A, Ippolito G, Agrati C; COVID 19 INMI Study Group. Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19. J Antimicrob Chemother. 2020 Oct 1;75(10):2977-2980. doi: 10.1093/jac/dkaa239. PMID: 32607555; PMCID: PMC7337789.
17: Humeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, Ling J, Vu A, German P. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin Transl Sci. 2020 Sep;13(5):896-906. doi: 10.1111/cts.12840. Epub 2020 Aug 5. PMID: 32589775; PMCID: PMC7361781.
18: Alvarez JC, Moine P, Etting I, Annane D, Larabi IA. Quantification of plasma remdesivir and its metabolite GS-441524 using liquid chromatography coupled to tandem mass spectrometry. Application to a Covid-19 treated patient. Clin Chem Lab Med. 2020 Jun 22;58(9):1461-1468. doi: 10.1515/cclm-2020-0612. PMID: 32573468.
19: Dickinson PJ, Bannasch M, Thomasy SM, Murthy VD, Vernau KM, Liepnieks M, Montgomery E, Knickelbein KE, Murphy B, Pedersen NC. Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats with clinically diagnosed neurological feline infectious peritonitis. J Vet Intern Med. 2020 Jul;34(4):1587-1593. doi: 10.1111/jvim.15780. Epub 2020 May 22. PMID: 32441826; PMCID: PMC7379040.
20: Avataneo V, de Nicolò A, Cusato J, Antonucci M, Manca A, Palermiti A, Waitt C, Walimbwa S, Lamorde M, di Perri G, D'Avolio A. Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS- CoV-2/COVID-19 and Ebola virus disease. J Antimicrob Chemother. 2020 Jul 1;75(7):1772-1777. doi: 10.1093/jac/dkaa152. PMID: 32361744; PMCID: PMC7197584.
Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats.
Note: Chemical structure was from MBio. 2018 Mar 6;9(2). pii: e00221-18. doi: 10.1128/mBio.00221-18.
For preparation of GS-441524 stock solution, customer may use below protocol, which was published
GS-441524 was diluted to a concentration of 10 or 15 mg/ml in 5% ethanol, 30% propylene glycol, 45% PEG 400, 20% water (pH 1.5 with HCl). The mixture was placed in sterile 50 ml glass injection bottles, agitated until in suspension, and then placed in a sonicated water bath for 5–20 mins until clear. The diluted drug was refrigerated and used within 3–4 weeks.