2. Academic Validation
  3. 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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161877
    Antiviral Agent
    RSV