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
posted on 2021-04-09, 18:35authored byRichard L. Mackman, Hon C. Hui, Michel Perron, Eisuke Murakami, Christopher Palmiotti, Gary Lee, Kirsten Stray, Lijun Zhang, Bindu Goyal, Kwon Chun, Daniel Byun, Dustin Siegel, Scott Simonovich, Venice Du Pont, Jared Pitts, Darius Babusis, Arya Vijjapurapu, Xianghan Lu, Cynthia Kim, Xiaofeng Zhao, Julie Chan, Bin Ma, Diane Lye, Adelle Vandersteen, Sarah Wortman, Kimberly T. Barrett, Maria Toteva, Robert Jordan, Raju Subramanian, John P. Bilello, Tomas Cihlar
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.