Prodrugs of a 1'-CN-4-Aza-7,9-dideazaadenosine -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

A discovery program targeting respiratory syncytial virus (RSV) identified -nucleoside (RSV A2 EC = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (, GS-5734) that is >30-fold more potent than against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, -, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of following molar normalized IV dosing of compared to that of . A once daily 10 mg/kg IV administration of in an African Green monkey RSV model demonstrated a >2-log reduction in the peak lung viral load. These early data following the discovery of supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.