Discovery of GS-7682, a Novel 4'-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys

  • J Med Chem. 2024 Jul 17. doi: 10.1021/acs.jmedchem.4c00899.
Dustin S Siegel  1 ,  Hon C Hui  1 ,  Jared Pitts  1 ,  Meghan S Vermillion  1  2 ,  Kazuya Ishida  1 ,  Davin Rautiola  1 ,  Michael Keeney  1 ,  Hammad Irshad  2 ,  Lijun Zhang  1 ,  Kwon Chun  1 ,  Gregory Chin  1 ,  Bindu Goyal  1 ,  Edward Doerffler  1 ,  Hai Yang  1 ,  Michael O Clarke  1 ,  Chris Palmiotti  1 ,  Arya Vijjapurapu  1 ,  Nicholas C Riola  1 ,  Kirsten Stray  1 ,  Eisuke Murakami  1 ,  Bin Ma  1 ,  Ting Wang  1 ,  Xiaofeng Zhao  1 ,  Yili Xu  1 ,  Gary Lee  1 ,  Bruno Marchand  1 ,  Minji Seung  1 ,  Arabinda Nayak  1 ,  Adrian Tomkinson  1 ,  Nani Kadrichu  3 ,  Scott Ellis  1 ,  Ona Barauskas  1 ,  Joy Y Feng  1 ,  Jason K Perry  1 ,  Michel Perron  1 ,  John P Bilello  1 ,  Philip J Kuehl  2 ,  Raju Subramanian  1 ,  Tomas Cihlar  1 ,  Richard L Mackman  1
Affiliations
  • 1. Gilead Sciences, Inc., Foster City, California 94404, United States.
  • 2. Lovelace Biomedical, Albuquerque, New Mexico 87108, United States.
  • 3. Inspired - Pulmonary Solutions, San Carlos, California 94070, United States.
PMID: 39018526 DOI: 10.1021/acs.jmedchem.4c00899
Abstract

Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad Antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and Enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.

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