Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4′-CN-4-Aza-7,9-DideazaadenosineC-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys

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 EC 50 = 3-46 nM, human metapneumovirus (hMPV) EC 50 = 210 ± 50 nM, human rhinovirus (RV) EC 50 = 54-61 nM, and enterovirus (EV) EC 50 = 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.