Prodrugs of a 1'-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV.
J Med Chem
; 64(8): 5001-5017, 2021 04 22.
Article
in English
| MEDLINE | ID: covidwho-1174625
ABSTRACT
A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Prodrugs
/
Adenosine Monophosphate
/
Respiratory Syncytial Virus, Human
/
Respiratory Syncytial Virus Infections
/
Alanine
Type of study:
Prognostic study
Topics:
Traditional medicine
Limits:
Animals
/
Humans
/
Male
Language:
English
Journal:
J Med Chem
Journal subject:
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Acs.jmedchem.1c00071
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