Journal of Medicinal Chemistry 2007-08-09

Liver-targeted prodrugs of 2'-C-methyladenosine for therapy of hepatitis C virus infection.

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

文献索引：J. Med. Chem. 50(16) , 3891-6, (2007)

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摘要

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%.