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

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• 作者：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. Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 9, 2007
• 年：2007
• 卷：50
• 期：16
• 页码：3891 - 3896
• 全文大小：128K
• 年卷期：v.50,no.16(August 9, 2007)
• ISSN：1520-4804

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%.