Synthesis and HCV inhibitory properties of 9-deaza- and 7,9-dideaza-7-oxa-2′-C-methyladenosine

As a part of an ongoing medicinal chemistry effort to identify inhibitors of the Hepatitis C Virus RNA replication, we report here the synthesis and biological evaluation of 9-deaza- and 7,9-dideaza-7-oxa-2′-C-methyladenosine. The parent 2′-C-methyladenosine shows excellent intracellular inhibitory activity but poor pharmacokinetic profile. Replacement of the nucleoside-defining 9-N of 2′-C-methyladenosine with a carbon atom was designed to yield metabolically more stable C-nucleosides. Modifications at position 7 were designed to exploit the importance of the hydrogen bond accepting properties of this heteroatom in modulating the adenosine deaminase (ADA) mediated 6-N deamination. 7-Oxa-7,9-dideaza-2′-C-methyladenosine was found to be a moderately active inhibitor of intracellular HCV RNA replication, whereas 9-deaza- 2′-C-methyladenosine showed only weak activity despite excellent overlap of both of the synthesized target compounds with 2′-C-methyladenosine’s three dimensional structure. Position 7 of the nucleobase proved to be an effective handle for modulating ADA-mediated degradation, with the rate of degradation correlating with the hydrogen-bonding properties at this position.

2′-C-Methyl analogs of 7-oxa- and 7-aza-7,9-dideazadenosines were synthesized and their metabolic stability as well as antiviral (HCV) properties evaluated.Figure optionsDownload as PowerPoint slide