Synthesis and evaluation of novel phosphoramidate prodrugs of 2′-methyl cytidine as inhibitors of hepatitis c virus NS5B polymerase

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…used this approach for the synthesis of 2′- C -Me-cytidine aryloxyphosphoramidate prodrugs bearing β-amino alcohols (Scheme 125). 216 2′- C -Me-cytidine was first protected with an isopropylidene group after treatment with 2,2-dimethoxypropane and p -TsOH in acetone in 80% yield. The protected nucleoside was reacted with diphenyl phosphite in pyridine followed by amino alcohol to give 429 in 40% yield over two steps.…”

Enhancement of intestinal absorption of 2-methyl cytidine prodrugs

“…Compound C1 was obtained by derivatization of 2′-methyl cytidine with phosphoramidate pro-drug moiety (Carroll et al, 2009;Donghi et al, 2009). Physico-chemical properties of compound C1 have been calculated using ACD/Labs (ACD/Labs Libraries version 12.01 and LogP Related Properties Algorithm ACD/Labs version B) and are summarized in Figure 2.…”

“…Hydrophilic essential cellular nutrients such as nucleosides are efficiently carried across these epithelial Gane et al (2008) barriers by specific transport systems (Majumdar & Mitra, 2006). Derivatization of 2′-methyl cytidine with phosphoramidate pro-drug moiety leading to C1 aimed to increase the liver levels of the nucleoside triphosphate (Carroll et al, 2009;Donghi et al, 2009), and was not completely effective in conferring appropriate permeability properties to the molecule.…”

“…We were recently involved in the discovery of novel phosphoramidate prodrugs of 2′-methyl-cytidine as potent and selective inhibitors of HCV replicon in cell culture (Donghi et al, 2009). The lead optimization of these pro-drugs was driven primarily by the ability of the compounds to form the in vivo active species, the nucleoside triphosphate, in the liver.…”

“…The lead optimization of these pro-drugs was driven primarily by the ability of the compounds to form the in vivo active species, the nucleoside triphosphate, in the liver. In particular, nucleoside triphosphate liver levels at 6 h post-dose were used as a ranking factor, because at this time point we observed the peak concentration of active drug in the target organ (Donghi et al, 2009). …”