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GS-443902 trisodium (GS-441524 trisodium), the trisodiume metabolite (active) of Remdesivir (GS-5734; Veklury) which is an FDA approved drug for treating COVID-19, is a novel highly potent viral RNA-dependent RNA-polymerases (RdRp) inhibitor with IC50s of 1.1 µM, 5 µM for RSV RdRp and HCV RdRp, respectively. It is the active triphosphate metabolite of Remdesivir.
| Targets |
RSV RdRp (IC50 = 1.1 µM); HCV RdRp (IC50 = 5 µM)
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|---|---|
| ln Vitro |
The levels of GS-443902 trisodium (GS-441524 trisodium triphosphate; remdesivir metabolite trisodium) were measured in macrophages, HMVEC, and HeLa cell lines, and the Cmax values were 300, 110, and 90 pmol/million cells, respectively [1]. Compound 8a, GS-443902 Trisodium, is a derivative of triphosphate (TP) [2]. GS-443902 trisodium (NTP; 0.01, 0.1, 1, 10, 100 μM) binds to nascent viral RNA transcripts, forcing them to terminate prematurely and inhibiting RSV RdRp-catalyzed RNA synthesis. After being successfully transformed into GS-443902 sodium within cells, GS-5734 specifically inhibits EBOV replication by targeting its RdRp and reducing viral RNA synthesis [3].
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| ln Vivo |
Remdesivir (GS-5734; 10 mg kg; IV) enters peripheral blood mononuclear cells (PBMC) quickly and, in rhesus monkeys, is significantly and efficiently converted to GS-443902 trisodium within 2 hours of administration (Remdesivir metabolism trisodium; NTP). With a half-life of 14 hours, GS-443902 trisodium is the primary metabolite in PBMC and reaches the levels needed for more than 50% viral suppression after 24 hours [3].
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| Animal Protocol |
The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.[2]
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| References |
[1]. Siegel D, et al. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. Med Chem. 2017 Mar 9;60(5):1648-1661.
[2]. Warren TK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016 Mar 17;531(7594):381-5. [3]. Cho A, et al. Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2705-7. |
| Additional Infomation |
The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016 , 531 , 381 - 385 ]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.[1]
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| Molecular Formula |
C12H12N5NA4O13P3
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|---|---|
| Molecular Weight |
619.129748344421
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| Exact Mass |
618.92352
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| CAS # |
1355050-21-3
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| Related CAS # |
GS-443902;1355149-45-9
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| PubChem CID |
139266778
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| Appearance |
Typically exists as white to light yellow solids at room temperature
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| tPSA |
301Ų
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| SMILES |
P(=O)([O-])(OP(=O)([O-])OP(=O)([O-])[O-])OC[C@@H]1[C@H]([C@H]([C@](C#N)(C2=CC=C3C(N)=NC=NN23)O1)O)O.[Na+].[Na+].[Na+].[Na+]
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| InChi Key |
GONGCFUOBMNVIT-ZTYDICHKSA-J
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| InChi Code |
InChI=1S/C12H16N5O13P3.4Na/c13-4-12(8-2-1-6-11(14)15-5-16-17(6)8)10(19)9(18)7(28-12)3-27-32(23,24)30-33(25,26)29-31(20,21)22;;;;/h1-2,5,7,9-10,18-19H,3H2,(H,23,24)(H,25,26)(H2,14,15,16)(H2,20,21,22);;;;/q;4*+1/p-4/t7-,9-,10-,12+;;;;/m1..../s1
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| Chemical Name |
tetrasodium;[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate
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| Synonyms |
GS-441524 sodium; 1355050-21-3; tetrasodium;[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate; GS-443902 Sodium; BCP29948; A937202; GS-441524; GS 441524; GS441524; GS 5734; GS-5734; GS5734
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. (3). This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~33.33 mg/mL (~55.82 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (83.73 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6152 mL | 8.0758 mL | 16.1517 mL | |
| 5 mM | 0.3230 mL | 1.6152 mL | 3.2303 mL | |
| 10 mM | 0.1615 mL | 0.8076 mL | 1.6152 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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