Prodrugs of a 1′-CN-4-Aza-7,9-dideazaadenosine <i>C</i>-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

Abstract

A discovery program targeting respiratory syncytial virus (RSV) identified <i>C</i>-nucleoside <b>4</b> (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 (<b>1</b>, GS-5734) that is >30-fold more potent than <b>4</b> against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, <b>1</b>-<b>NTP</b>, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of <b>1-NTP</b> following molar normalized IV dosing of <b>1</b> compared to that of <b>4</b>. A once daily 10 mg/kg IV administration of <b>1</b> 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 <b>1</b> supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.