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. 2021 Apr 22;64(8):5001-5017. doi: 10.1021/acs.jmedchem.1c00071.
Richard L Mackman  1 ,  Hon C Hui  1 ,  Michel Perron  1 ,  Eisuke Murakami  1 ,  Christopher Palmiotti  1 ,  Gary Lee  1 ,  Kirsten Stray  1 ,  Lijun Zhang  1 ,  Bindu Goyal  1 ,  Kwon Chun  1 ,  Daniel Byun  1 ,  Dustin Siegel  1 ,  Scott Simonovich  1 ,  Venice Du Pont  1 ,  Jared Pitts  1 ,  Darius Babusis  1 ,  Arya Vijjapurapu  1 ,  Xianghan Lu  1 ,  Cynthia Kim  1 ,  Xiaofeng Zhao  1 ,  Julie Chan  1 ,  Bin Ma  1 ,  Diane Lye  1 ,  Adelle Vandersteen  1 ,  Sarah Wortman  1 ,  Kimberly T Barrett  1 ,  Maria Toteva  1 ,  Robert Jordan  1 ,  Raju Subramanian  1 ,  John P Bilello  1 ,  Tomas Cihlar  1
Affiliations
  • 1. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 33835812 DOI: 10.1021/acs.jmedchem.1c00071
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.