GS-441524
[CAS# 1191237-69-0]

Identification

• Classification: Biochemical >> Nucleoside drugs
• Name: GS-441524
• Synonyms: (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile
• Molecular Formula: C₁₂H₁₃N₅O₄
• Molecular Weight: 291.26
• CAS Registry Number: 1191237-69-0
• EC Number: 857-885-9
• SMILES: C1=C2C(=NC=NN2C(=C1)[C@]3([C@@H]([C@@H]([C@H](O3)CO)O)O)C#N)N

Properties

• Solubility: Slightly soluble (1.9 g/L) (25 ºC), Calc.^*
• Density: 1.84±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*
• Index of refraction: 1.818 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS07;GHS08 Danger
• Hazard Statements: H315-H317-H318-H334-H335-H341-H361-H371
• Precautionary Statements: P203-P233-P260-P261-P264-P264+P265-P270-P271-P272-P280-P284-P302+P352-P304+P340-P305+P354+P338-P308+P316-P317-P318-P319-P321-P332+P317-P333+P317-P342+P316-P362+P364-P403-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin sensitization	Skin Sens.	1	H317
Respiratory sensitization	Resp. Sens.	1	H334
Specific target organ toxicity - single exposure	STOT SE	3	H335
Reproductive toxicity	Repr.	2	H361
Germ cell mutagenicity	Muta.	2	H341
Serious eye damage	Eye Dam.	1	H318
Skin irritation	Skin Irrit.	2	H315

Discovory and Applicatios

GS-441524 is a nucleoside analog that has attracted significant attention due to its antiviral activity, particularly as the parent nucleoside of remdesivir (GS-5734). It belongs to the class of adenosine analogs and was originally developed by Gilead Sciences as part of efforts to design broad-spectrum antiviral agents. Structurally, GS-441524 consists of an adenosine-like base attached to a modified ribose sugar, with specific substitutions that enable inhibition of viral RNA-dependent RNA polymerases (RdRp).

The discovery of GS-441524 occurred during antiviral research programs in the early 2000s, in which libraries of nucleoside analogs were screened for activity against emerging RNA viruses. GS-441524 demonstrated strong in vitro efficacy against coronaviruses, filoviruses, and other RNA viruses by acting as a chain terminator during viral RNA synthesis. Its potency and broad-spectrum profile led to further development of prodrug derivatives designed to enhance cellular uptake and metabolic activation. This work resulted in remdesivir, which was advanced to clinical development and emergency therapeutic use during the COVID-19 pandemic.

Despite remdesivir’s prominence, GS-441524 itself has been the subject of increasing interest because it is the major circulating metabolite of remdesivir in humans and animals. Pharmacokinetic studies have shown that remdesivir is rapidly hydrolyzed and metabolized to GS-441524 after administration, and the latter persists in plasma with measurable antiviral activity. This observation has prompted discussions about whether GS-441524 could be developed directly as an oral or parenteral therapeutic agent.

In veterinary medicine, GS-441524 has already found practical application. It has been used as an investigational treatment for feline infectious peritonitis (FIP), a fatal disease in cats caused by a coronavirus. Clinical reports and controlled studies have demonstrated that GS-441524 can induce remission and significantly improve survival rates in cats with FIP, a breakthrough in the treatment of a disease that previously had no effective therapy. This veterinary success has further fueled interest in potential human applications.

The mechanism of action of GS-441524 mirrors that of remdesivir, with incorporation of its triphosphate form into viral RNA leading to premature termination of replication. Its antiviral spectrum includes coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2, as well as other RNA viruses tested in preclinical systems. However, despite strong laboratory and animal data, GS-441524 has not been developed into an approved drug for human use, partly due to intellectual property and regulatory considerations.

Research on GS-441524 continues, with a focus on optimizing its formulation, bioavailability, and pharmacokinetic properties. Comparisons between GS-441524 and remdesivir suggest that the nucleoside analog may offer advantages in stability and administration, although direct clinical evidence in humans remains limited. Its story exemplifies how parent nucleoside compounds can serve as both active agents and precursors for more complex prodrugs, contributing to the advancement of antiviral therapy.

References

2024. Differential Bioactivation Profiles of Different GS-441524 Prodrugs in Cell and Mouse Models: ProTide Prodrugs with High Cell Permeability and Susceptibility to Cathepsin A Are More Efficient in Delivering Antiviral Active Metabolites to the Lung. Journal of Medicinal Chemistry, 67(9).
DOI: 10.1021/acs.jmedchem.4c00234
URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11246197

2024. First analytical confirmation of drug-induced crystal nephropathy in felines caused by GS-441524, the active metabolite of Remdesivir. Journal of Pharmaceutical and Biomedical Analysis, 248.
DOI: 10.1016/j.jpba.2024.116248
URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229044

2017. 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. Journal of Medicinal Chemistry, 60(5).
DOI: 10.1021/acs.jmedchem.6b01594
URL: https://pubmed.ncbi.nlm.nih.gov/28124907