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.
Mackman RL, Hui HC, Perron M, Murakami E, Palmiotti C, Lee G, Stray K, Zhang L, Goyal B, Chun K, Byun D, Siegel D, Simonovich S, Du Pont V, Pitts J, Babusis D, Vijjapurapu A, Lu X, Kim C, Zhao X, Chan J, Ma B, Lye D, Vandersteen A, Wortman S, Barrett KT, Toteva M, Jordan R, Subramanian R, Bilello JP, Cihlar T.
A discovery program targeting respiratory syncytial virus (RSV) identified <i>C</i>-nucleoside <b>4</b> (RSV A2 EC<sub>50</sub> = 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-log<sub>10</sub> 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.