1. 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
- Author
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Siegel, Dustin S., Hui, Hon C., Pitts, Jared, Vermillion, Meghan S., Ishida, Kazuya, Rautiola, Davin, Keeney, Michael, Irshad, Hammad, Zhang, Lijun, Chun, Kwon, Chin, Gregory, Goyal, Bindu, Doerffler, Edward, Yang, Hai, Clarke, Michael O., Palmiotti, Chris, Vijjapurapu, Arya, Riola, Nicholas C., Stray, Kirsten, Murakami, Eisuke, Ma, Bin, Wang, Ting, Zhao, Xiaofeng, Xu, Yili, Lee, Gary, Marchand, Bruno, Seung, Minji, Nayak, Arabinda, Tomkinson, Adrian, Kadrichu, Nani, Ellis, Scott, Barauskas, Ona, Feng, Joy Y., Perry, Jason K., Perron, Michel, Bilello, John P., Kuehl, Philip J., Subramanian, Raju, Cihlar, Tomas, and Mackman, Richard L.
- 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 vitroand in vivo. 1demonstrated 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 1and its analogues as potential therapeutics for pneumo- and picornaviruses.
- Published
- 2024
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