1. Academic Validation
  2. 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.
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
    抗病毒剂
    RSV