1191237-69-0 Usage
Description
Different sources of media describe the Description of 1191237-69-0 differently. You can refer to the following data:
1. GS-441524 is a nucleoside analogue that terminates the RNA chain of viral RNA-dependent RNA polymerase.
GS-441524 was developed by Gilead Sciences, Inc as part of their research into human RNA virus disease such as Ebola.
GS-441524 is a small molecule that exhibits potent antiviral activity against a number of RNA viruses, including the zoonotic severe acute respiratory syndrome (SARS) coronavirus ( Cho et al., 2012). A phosphoramidate prodrug of GS-441524 (GS-5734) has been previously shown to inhibit the replication of several taxonomically diverse RNA viruses such as Middle East respiratory syndrome virus, Ebola virus, Lassa fever virus, Junin virus and respiratory syncytial virus, while having low cytotoxicity in a wide-range of cell lines ( Sheahan et al., 2017 ). GS-5734 has also been shown to protect rhesus monkeys from experimental Ebola virus infection ( Warren et al., 2016 ).
2. GS-441524 is the active prodrug of the broad-spectrum antiviral Remdesivir. GS-441524 is an adenosine nucleotide analog in viral RNA production. It is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). The compound interferes with the action of viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production (RNA synthesis arrest), either by terminating RNA chains or causing mutations. It inhibits MERS-CoV or SARS-CoV-infected HAE cultures (EC50=74nM and 69nM) and murine hepatitis virus (MHV) (EC50=30nM). In vivo, remdesivir (25 and 50 mg/kg) reduces lung viral titers and prevents weight loss in a mouse model of SARS-CoV infection. Remdesivir is used as a treatment for Ebola virus disease and Marburg virus infections and other single stranded RNA viruses such as respiratory syncytial virus, Junin virus, Lassa fever virus, Nipah virus, Hendra virus and the coronaviruses (including MERS and SARS viruses). Remdesivir is effective in the control of 2019-nCoV (COVID-19) infection in vitro. It now also has been studied as potential treatment of SARS-CoV-2 infections.
Mechanism of action
GS-441524 requires intracellular phosphorylation via cellular kinases to a nucleoside monophosphate and subsequently to the active triphosphate metabolite (NTP) ( Cho et al., 2012 ; Sheahan et al., 2017; Warren et al., 2016). The active NTP analog functions as a competitor of the natural nucleoside triphosphates in viral RNA synthesis. The active form of GS-441524 has been shown to inhibit RSV RNA-dependent RNA polymerase mediated transcription by incorporating into the nascent viral transcript and causing premature termination ( Sheahan et al., 2017 ). We hypothesized that GS-441524 would be activated in feline cells, attenuate FIPV replication, have low cytotoxicity in feline cells in vitro and effectively treat cats with experimentally induced FIP.
Pharmacokinetics
A pharmacokinetic (PK) study was performed in laboratory cats to determine the metabolism and acute animal toxicity of GS-441524. GS-441524 was dissolved at a concentration of 12.5 mg/ml in 5% ethanol, 30% propylene glycol, 45% PEG 400, 20% water, and adjusted to pH 1.9 with concentrated HCl. Six laboratory cats were randomly divided into group A (n = 3; IV administration) or B (n = 3; SC administration). At time point zero, Group A cats were administered 5 mg compound/kg body weight intravenously while Group B cats received 5 mg com- pound/kg subcutaneously. Cats were then monitored for signs of acute toxicity (elevated pulse, respiratory distress, cyanosis, diarrhea, anorexia, drooling, vomiting, ataxia, weight loss, and changes in rectal temperature) daily for five days. Serial 0.5 ml whole blood samples in EDTA were obtained by lateral saphenous, superficial brachial or jugular venipuncture from each cat at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h. After collection, blood samples were immediately placed onice and then centrifuged at 5000 rpm for 5 min. The isolated plasma was pipetted into a 1.5 ml microcentrifuge tube and frozen at ? 70 °C for further analysis of free GS-441524. The buffy coat fraction from each blood collection was suspended in 1.5 ml phosphate free Tris-buffered saline (TBS, 50 mM Tris-Cl, pH 7.5, 150 mM NaCl) and PBMC isolated by Ficoll Hypaque density gradient centrifugation. The plasma and PBMC fractions were snap frozen in liquid nitrogen and shipped on dry ice to Gilead Sciences, Inc. (Foster City, CA) for further analyses. (plasma drug concentration and intracellular phosphorylation analyses).
Uses
GS-441524 is originally identified as an active metabolite of Remdesivir that is an antiviral drug, a novel nucleotide analog prodrug.
Acquired resistance
Resistance to GS-441524 can exist at the time of diagnosis, but this is uncommon. Rather, it tends to occur during treatment and is often partial at first and necessitates a higher dosage to accommodate for it. It can become total in some cats. Resistance is the biggest problem in cats with neurological disease, especially those that present with neurological disease or develop brain infections during treatment or during a relapse after what appears to have been a successful treatment. Many cats with partial drug resistance can be treated for their disease signs but will relapse as soon as the treatment is stopped. There have been cats "treated" for FIP for over a year with no cure, but ultimately resistance becomes worse or the owner runs out of money.
Biological Activity
GS 441524 is a viral RNA-dependent RNA polymerase (RdRp) inhibitor and broad spectrum antiviral nucleotide; active metabolite of Remdesivir. Competes with natural nucleoside triphosphates, blocking viral RNA synthesis. Exhibits antiviral activity against viruses from Coronaviridae family including SARS-CoV-2 in vitro, and SARS-CoV and feline infectious peritonitis virus (FIPV) in vitro and in vivo. Inhibits SARS-CoV and MERS-CoV- infected HAE cultures (EC50 values are 0.18 and 0.86 μM, respectively) and inhibits murine hepatitis virus (MHV) (EC50 = 1.1 μM).
Side effects
GS-441524 treatment is amazingly free of systemic side effects. It can cause minor kidney damage in some cats, but this does not progress to overt renal disease. Systemic drug reactions of the vasculitis type have been seen in a few cats and can be confused with injection site reactions. However, these drug reactions are at non-injection sites and are often self-limiting or respond well to a short-term low dose of steroids. The major side-effect of GS treatment is pain at the injection sites, which varies from cat to cat and according to the injection prowess of the person doing the treatment (usually the owner). Injection site sores are a problem with some owners and usually occur when the injection site is not moved around the body (stay away from between the shoulders) and not given into the muscle and nerve layers below the subcutis. I recommend selecting sites starting an inch behind the shoulder blades, down the back to 1-2 inches before the tailhead, and one third to one-half of the way down the chest and abdomen. Many people use gabapentin before injections to help ease the pain. Injection site sores are cleared of surrounding hair and gently cleaned 4 or more times a day with sterile cotton balls soaked in 1:5 dilution of household hydrogen peroxide. They usually do not require any more sophisticated treatment and heal within 2 weeks or so.
Preparation and handling
GS-441524 is supplied as a solid. A stock solution may be made by dissolving the GS-441524 in the solvent of choice, which should be purged with an inert gas. GS-441524 is soluble in organic solvents such as DMSO and dimethyl formamide. The solubility of GS-441524 in these solvents is approximately 10 mg/ml. GS-441524 is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, GS-441524 should first be dissolved in DMSO and then diluted with the aqueous buffer of choice. GS-441524 has a solubility of approximately 0.16 mg/ml in a 1:5 solution of DMSO:PBS (pH 7.2) using this method. We do not recommend storing the aqueous solution for more than one day.
References
1) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys: T.K. Warren, et al.; Nature 531, 381 (2016) 2) Late Ebola virus relapse causing meningoencephalitis: a case report: M. Jacobs, et al.; Lancet 388, 498 (2016) 3) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses: T.P. Sheahan, et al.; Sci. Transl. Med. 9, eaal3653 (2017) 4) 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; D. Siegel, et al.; J. Med. Chem. 60, 1648 (2017) 5) Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease: M.L. Agostini, et al.; mBio 9, e00221 (2018) 6) Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir: E.P. Tchesnokov, et al.; Viruses 11, E326 (2019) 7) Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge: M.K. Lo, et al.; Sci. Transl. Med. 11, eaau9242 (2019) 8) Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase: A.J. Brown, et al.; Antiviral Res. 169, 104541 (2019) 9) Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection: R. de Wit, et al.; PNAS (Epub ahead of print) (2020) 10) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro: M. Wang, et al.; Cell Res. 30, 269 (2020)
Check Digit Verification of cas no
The CAS Registry Mumber 1191237-69-0 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,1,9,1,2,3 and 7 respectively; the second part has 2 digits, 6 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 1191237-69:
(9*1)+(8*1)+(7*9)+(6*1)+(5*2)+(4*3)+(3*7)+(2*6)+(1*9)=150
150 % 10 = 0
So 1191237-69-0 is a valid CAS Registry Number.
1191237-69-0Relevant articles and documents
Preparation process of ridecevir mother nucleus intermediate
-
Paragraph 0025-0026; 0028; 0030; 0039-0040; 0042, (2021/10/27)
The invention discloses a preparation process of a ridecevir mother nucleus intermediate (3aR,4R,6S,6aS)-6-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxo-4-yl)methanol. The preparation method comprises the following steps: carrying out a coupling reaction on a pyrrole triazine halide II serving as a raw material and a halide III under the promotion of a metal reagent MX to obtain a coupling product IV with high stereoselectivity; and carrying out a free radical reaction on the IV and a cyaniding reagent in the presence of an oxidizing agent, and carrying out a boron trichloride debenzylation reaction on the obtained intermediate to obtain the ridecevir mother nucleus intermediate I with high stereoselectivity. The method has the main beneficial effects that the process route is relatively short, the reaction condition is mild, tedious procedures such as strong acidity and column chromatography separation and purification are avoided from the source, the reaction yield is high, the stereoselectivity is good, the method is easy to industrialize, and the method has relatively high implementation value and social and economic benefits.
N-protected heterocyclic compound, preparation method thereof and method for preparing C-nucleoside derivative by using N-protected heterocyclic compound
-
Paragraph 0442; 0443; 0444, (2021/08/14)
The invention provides an N-protected heterocyclic compound, a preparation method thereof and a method for preparing a C-nucleoside derivative by using the N-protected heterocyclic compound. Specifically, the invention provides a method for preparing the C-nucleoside derivative by using a heterocyclic compound protected by N-carbobenzoxy or N-tert-butyloxycarboryl. According to the method, halogenation is not needed, temporary amino protection is not needed, protons of the heterocyclic compound are removed by directly using an organic lithium or organic magnesium compound, and addition with ribose lactone is carried out. According to the method, the synthesis route of the C-nucleoside derivative is shortened, and the yield of the reaction of the heterocyclic compound and the ribose lactone is remarkably improved under the condition that no halogen atom is used as a substituent group.
Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2
Wei, Daibao,Hu, Tianwen,Zhang, Yumin,Zheng, Wei,Xue, Haitao,Shen, Jingshan,Xie, Yuanchao,Aisa, Haji A.
, (2021/08/27)
The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two L-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3′-isobutyryl ester 5a, the 5′-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.
