Discovery of GS-7682, a Novel 4′-Cyano-Modified <i>C</i>-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys
Dustin S. Siegel, Hon C. Hui, Jared Pitts, Meghan S. Vermillion, Kazuya Ishida, Davin Rautiola, Michael Keeney, Hammad Irshad, Lijun Zhang, Kwon Soo Chun, Gregory Chin, Bindu Goyal, Edward Doerffler, Hai Yang, Michael O. Clarke, Chris Palmiotti, Arya Vijjapurapu, Nicholas C. Riola, Kirsten M. Stray, Eisuke Murakami, Bin Ma, Ting Wang, Xiaofeng Zhao, Yili Xu, Gary Lee, Bruno Marchand, Minji Seung, Arabinda Nayak, Adrian Tomkinson, Nani Kadrichu, Scott Ellis, Ona Barauskas, Joy Y. Feng, Jason K. Perry, Michel Perron, John P. Bilello, Philip J. Kuehl, Raju Subramanian, Tomáš Cihlář, Richard L. Mackman
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 (EC 50 = 3–46 nM), human metapneumovirus (EC 50 = 210 nM), human rhinovirus (EC 50 = 54–61 nM), and enterovirus (EC 50 = 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.