The phosphoramidate ProTide approach greatly enhances the activity of β-2′-C-methylguanosine against hepatitis C virus

Design, Synthesis and Antiviral Evaluation of 2′- C -Methyl Branched Guanosine Pronucleotides: The Discovery of IDX184, a Potent Liver-Targeted HCV Polymerase Inhibitor

“…Furthermore, 2 also showed significant potency when radioactive natural triphosphates other than its competitor were used (IC 50 = 1.7 μM using 33 P-UTP; IC 50 = 1.2 μM using 33 P-CTP; and IC 50 = 1.5 μM using 33 P-ATP). As a general rule, the values presented in Table 1 are in agreement with the scattered values gathered from the literature [26][27][28][29][30][31][32]. It is noteworthy that 2′-MeG 1, which was reported to show oral bioavailability of 82% in rats [28], has moderate activity in replicon assays, while its triphosphate is a potent inhibitor of NS5B in HCV RdRp enzymatic assays.…”

INX-08189, a Phosphoramidate Prodrug of 6- O -Methyl-2′- C -Methyl Guanosine, Is a Potent Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic and Pharmacodynamic Properties

“…This approach facilitates the direct delivery of the monophosphorylated nucleoside analogue into the cell, bypassing the first rate-limiting phosphorylation step (4). The phosphoramidate prodrug strategy has been used successfully to improve the HCV antiviral potency of several modified nucleosides (14,19,25,27). In the case of 2Ј-C-MeG, a striking improvement in cell-based potency over that of the parent nucleoside can be achieved (Ͼ80 fold) with phosphoramidates incorporating 1-naphthyl as the aryl-leaving group (27).…”

“…The phosphoramidate prodrug strategy has been used successfully to improve the HCV antiviral potency of several modified nucleosides (14,19,25,27). In the case of 2Ј-C-MeG, a striking improvement in cell-based potency over that of the parent nucleoside can be achieved (Ͼ80 fold) with phosphoramidates incorporating 1-naphthyl as the aryl-leaving group (27). These prodrugs of 2Ј-C-MeG also have been shown to generate high concentrations of the active 2Ј-C-MeG triphosphate in liver tissue following oral administration in mice (24).…”

The search for nucleoside/nucleotide analog inhibitors of dengue virus

“…To overcome the bottleneck of first kinase phosphorylation, various phosphate/phosphonate prodrugs have been developed McGuigan et al, 2009a;Perrone et al, 2007;Ray and Hostetler, 2011). In the past decade, there is a trend towards developing nucleoside prodrugs with phosphonate/phosphate group to overcome the limitations associated with the first phosphorylation (McGuigan et al, 2009b(McGuigan et al, , 2005. This approach has turned some inactive nucleosides into potent inhibitors or has improved compound efficacy by increasing the intracellular nucleoside triphosphate concentration.…”