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 PMID: 39018526

Target-related Cytokines

2026-09-23

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

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.