GS-441524

Details:

GS-441524 Chemical Properties
density     1.84±0.1 g/cm3(Predicted)
pka    12.13±0.70(Predicted)
CAS DataBase Reference    1191237-69-0
Safety Information
MSDS Information
GS-441524 Usage And Synthesis
Description    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 ).
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).