{Reference Type}: Journal Article
{Title}: 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}: Siegel DS;Hui HC;Pitts J;Vermillion MS;Ishida K;Rautiola D;Keeney M;Irshad H;Zhang L;Chun K;Chin G;Goyal B;Doerffler E;Yang H;Clarke MO;Palmiotti C;Vijjapurapu A;Riola NC;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 JY;Perry JK;Perron M;Bilello JP;Kuehl PJ;Subramanian R;Cihlar T;Mackman RL;
{Journal}: J Med Chem
{Volume}: 67
{Issue}: 15
{Year}: 2024 Aug 8
{Factor}: 8.039
{DOI}: 10.1021/acs.jmedchem.4c00899
{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.