文摘
2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV)subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate(NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation byadenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination,we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP),anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compoundsidentified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive ofefficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore,additional analogues were synthesized and screened for liver NTP levels after oral administration to rats.Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.