(2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile,

GS-441524,Remdesivir intermediate 

(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile, 1′-cyano-4-aza-7,9-dideazaadenosine,

Nucleoside analog with antiviral activity against zoonotic feline infectious peritonitis virus (FIPV) and severe acute respiratory syndrome (SARS) virus from Coronaviridae family. The compound is a pro-drug and undergoes intracellular phosphorylation resulting in the active triphosphate metabolite. The triphosphorylated GS 441524 analog competes with natural nucleoside triphosphates and interferes with viral RNA synthesis. In previous studies it was tested in vitro as well as in experimental animals and showed good safety profile.

The GS-441524 nucleoside analog is an antiviral drug that was created in collaboration with Gilead Sciences. It is the principal plasma metabolite of prodrug that fights viruses, remdesivir. It has a half-life of approximately 24-hours in humans patients.GS-441524 and GS-441524 were both proven that they are effective when tested in vitro on feline coronavirus variants responsible of feline infection peritonitis (FIP) which is a fatal cat-related systemic disease. Remdesivir was not tested on cats (though some vets offer it) However, GS-441524 is been proven to be a successful therapy for FIP and is used widely even though there is not having official FDA approval because of Gilead's inability to approve the drug for use in the treatment of veterinary.

The uses of the GS-441524

GS-441524 is used for pet owners who want to cure their cats with FIP However, Gilead Sciences has refused to allow the drug to be licensed for veterinary usage. The effectiveness of the drug for this purpose has been demonstrated conclusively through multiple studies that included field studies, and even when it comes to more complicated varieties of FIP like those that have neurological or multisystemic involvement.

GS-441524 was administered directly in healthy humans, with the high plasma concentrations, with 12 uM being achieved that is 10 times the amount required to fight SARS-CoV-2 the culture.

Research conducted on the GS-441524

The GS-441524 drug is comparable to or even more potent than the remdesivir drug against SARS-CoV-2 in cells culture.Specific benefits cited are easy synthesis, lower renal and hepatotoxicity and the possibility of oral administration (which is incompatible with the remdesivir drug due to its low hepatic stability and first-pass metabolism).Direct effectiveness against SARS-CoV-2 has been observed using a mouse model of COVID-19.A deuterium-modified version of GS-441524 is being developed and has been shown to be effective in preclinical studies in both cell and mouse models, by a team comprised of members from the Wuhan Institute of Virology.

Pharmacodynamics of GS-41524

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. The triphosphate in GS-441524, it is also the biologically active anti-viral compound produced by remdesivir. However, it is produced by a different biochemical mechanism than the earlier.

Intracellular triple-phosphorylation of GS-441524 yields its active 1'-cyano-substituted adenosine triphosphate analogue, which directly disrupts viral RNA replication by competing with endogenous NTPs for incorporation into nascent viral RNA transcripts and triggering delayed chain termination of RNA-dependent RNA polymerase.

Pharmacokinetics of the GS-441524

The GS-441524 1'-cyano-substituted A analog. It is remdesivir's predominant metabolite circulating in the serum due to rapid hydrolysis (half life less than 1 hour) followed by dephosphorylation.The elimination half-life of GS-441524 is around 2 hours in cynomolgus, much shorter than the 24 hours reported in humans. The longer half-life suggests a daily dose in the event that the drug is accepted for oral use by humans.