GS-441524

Identification

Summary

GS-441524 is an experimental nucleoside analog antiviral investigated for its use in the treatment of Ebola and SARS-CoV-2 infections.

Generic Name
GS-441524
DrugBank Accession Number
DB15686
Background

GS-441524 is an adenosine nucleotide analog antiviral, similar to remdesivir.2,5 This molecule was patented in 2009.6 In vitro studies of GS-441524 have determined it has a higher EC50 than remdesivir against a number of viruses, meaning GS-441524 is less potent.2,2 GS-441524 continues to be studied in the treatment of Feline Infectious Peritonitis Virus, a coronavirus that only infects cats.1

Type
Small Molecule
Groups
Experimental
Structure
Thumb
Weight
Average: 291.267
Monoisotopic: 291.096753919
Chemical Formula
C12H13N5O4
Synonyms
Not Available
External IDs
  • EVO 984
  • EVO-984
  • EVO984
  • GS-441524
  • GS441524

Pharmacology

Indication

Not Available

Pharmacology
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Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

GS-441524 is phosphorylated 3 times to form the active nucleoside triphosphate, which is incorporated into the genome of virions, terminating its replication.2

TargetActionsOrganism
UReplicase polyprotein 1ab
inhibitor
SARS-CoV
URNA-directed RNA polymerase L
inhibitor
Zaire ebolavirus (strain Mayinga-76)
Absorption

GS-441524 has been found to transport poorly into cells compared to remdesivir.2,3,4

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

GS-441524 is phosphorylated 3 times to form the active nucleoside triphosphate.2

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with GS-441524.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with GS-441524.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with GS-441524.
Bacillus calmette-guerin substrain russian BCG-I live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with GS-441524.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with GS-441524.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with GS-441524.
Human adenovirus e serotype 4 strain cl-68578 antigenThe therapeutic efficacy of Human adenovirus e serotype 4 strain cl-68578 antigen can be decreased when used in combination with GS-441524.
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with GS-441524.
Typhoid Vaccine LiveThe therapeutic efficacy of Typhoid Vaccine Live can be decreased when used in combination with GS-441524.
Varicella zoster vaccine (live/attenuated)The therapeutic efficacy of Varicella zoster vaccine (live/attenuated) can be decreased when used in combination with GS-441524.
Interactions
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Food Interactions
Not Available

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
1BQK176DT6
CAS number
1191237-69-0
InChI Key
BRDWIEOJOWJCLU-LTGWCKQJSA-N
InChI
InChI=1S/C12H13N5O4/c13-4-12(10(20)9(19)7(3-18)21-12)8-2-1-6-11(14)15-5-16-17(6)8/h1-2,5,7,9-10,18-20H,3H2,(H2,14,15,16)/t7-,9-,10-,12+/m1/s1
IUPAC Name
(2R,3R,4S,5R)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile
SMILES
NC1=NC=NN2C1=CC=C2[C@@]1(O[C@H](CO)[C@@H](O)[C@H]1O)C#N

References

General References
  1. Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, Liepnieks M, Pedersen NC: The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet Microbiol. 2018 Jun;219:226-233. doi: 10.1016/j.vetmic.2018.04.026. Epub 2018 Apr 22. [Article]
  2. Amirian ES, Levy JK: Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health. 2020 Mar 27;9:100128. doi: 10.1016/j.onehlt.2020.100128. eCollection 2020 Jun. [Article]
  3. Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, Flint M, McMullan LK, Siegel D, Clarke MO, Mackman RL, Hui HC, Perron M, Ray AS, Cihlar T, Nichol ST, Spiropoulou CF: GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep. 2017 Mar 6;7:43395. doi: 10.1038/srep43395. [Article]
  4. de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, Scott D, Cihlar T, Feldmann H: Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020 Feb 13. pii: 1922083117. doi: 10.1073/pnas.1922083117. [Article]
  5. FDA: Fact Sheet For Health Care Providers EUA of Remdesivir [Link]
  6. European Patent Specification: 1'-substituted carba-nucleoside analogs for antiviral treatment [Link]
ChemSpider
28499294
ChEBI
147281
ChEMBL
CHEMBL2016757
ZINC
ZINC000084586789
PDBe Ligand
U08
Wikipedia
GS-441524
PDB Entries
7bf6

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility13.1 mg/mLALOGPS
logP-0.58ALOGPS
logP-1.9ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)12.13ChemAxon
pKa (Strongest Basic)0.65ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area149.92 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity81.95 m3·mol-1ChemAxon
Polarizability26.99 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
SARS-CoV
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Replicase polyprotein 1ab: Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.Host transl...
Gene Name
rep
Uniprot ID
P0C6X7
Uniprot Name
Replicase polyprotein 1ab
Molecular Weight
790241.63 Da
References
  1. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR: Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. doi: 10.1128/mBio.00221-18. [Article]
Kind
Protein
Organism
Zaire ebolavirus (strain Mayinga-76)
Pharmacological action
Unknown
Actions
Inhibitor
General Function
RNA-directed RNA polymerase that catalyzes the transcription of viral mRNAs, their capping and polyadenylation. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). The viral polymerase binds to the genomic RNA at the 3' leader promoter, and transcribes subsequently all viral mRNAs with a decreasing efficiency. The first gene is the most transcribed, and the last the least transcribed. The viral phosphoprotein acts as a processivity factor. Capping is concommitant with initiation of mRNA transcription. Indeed, a GDP polyribonucleotidyl transferase (PRNTase) adds the cap structure when the nascent RNA chain length has reached few nucleotides. Ribose 2'-O methylation of viral mRNA cap precedes and facilitates subsequent guanine-N-7 methylation, both activities being carried by the viral polymerase. Polyadenylation of mRNAs occur by a stuttering mechanism at a slipery stop site present at the end viral genes. After finishing transcription of a mRNA, the polymerase can resume transcription of the downstream gene.
Specific Function
Atp binding
Gene Name
L
Uniprot ID
Q05318
Uniprot Name
RNA-directed RNA polymerase L
Molecular Weight
252722.045 Da
References
  1. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019 Dec 11. doi: 10.1056/NEJMoa1914510. [Article]

Drug created on May 19, 2020 16:55 / Updated on June 12, 2020 16:53