Siegel, D. S.; Hui, H. C.; Pitts, J.; Vermillion, M. S.; Ishida, K.; Rautiola, D.; Keeney, M.; Irshad, H.; Zhang, L.; Chun, K.; Chin, G.; Goyal, B.; Doerffler, E.; Yang, H.; Clarke, M. O.; Palmiotti, C.; Vijjapurapu, A.; Riola, N. C.; Stray, K.; Murakami, E.; Ma, B.; Wang, T.; Zhao, X.; Xu, Y.; Lee, G.; Marchand, B.; Seung, M.; Nayak, A.; Tomkinson, A.; Kadrichu, N.; Ellis, S.; Barauskas, O.; Feng, J. Y.; Perry, J. K.; Perron, M.; Bilello, J.; Kuehl, P. J.; Subramanian, R.; Cihlar, T.; Mackman, R. L.

Acute respiratory viral infections (ARVI), 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 (hMPV) EC50 = 210 +/- 50 nM, human rhinovirus (RV) EC50 = 54-61 nM, and enterovirus (EV) EC50 = 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5\'-methyl((S)-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2\',3\'-diisobutyrate promoieties as optimal for high 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 finding support additional evaluation of 1 and its analogs as a potential therapeutic for pneumo- and picornaviruses.