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Liver-Targeted Prodrugs of 2‘-C-Methyladenosine for Therapy of Hepatitis C Virus Infection

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journal contribution
posted on 09.08.2007, 00:00 by Scott J. Hecker, K. Raja Reddy, Paul D. van Poelje, Zhili Sun, Wenjian Huang, Vaibhav Varkhedkar, M. Venkat Reddy, James M. Fujitaki, David B. Olsen, Kenneth A. Koeplinger, Serge H. Boyer, David L. Linemeyer, Malcolm MacCoss, Mark D. Erion
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 by adenosine 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 compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy 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%.