Synthesis and Evaluation of 2,6-Modified Purine 2'-C-Methyl Ribonucleosides as Inhibitors of HCV Replication.

A variety of 2,6-modified purine 2'-C-methylribonucleosides and their phosphoramidate prodrugs were synthesized and evaluated for inhibition of HCV RNA replication in Huh-7 cells and for cytotoxicity in various cell lines. Cellular pharmacology and HCV polymerase incorporation studies on the most potent and selective compound are reported.

Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors.

Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50=0.8 µM).

Synthesis and evaluation of non-dimeric HCV NS5A inhibitors.

Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).

Characterization of hepatitis B virus inhibition by novel 2'-fluoro-2',3'-unsaturated beta-D- and L-nucleosides.

The clinical emergence of lamivudine and adefovir resistance mutations on prolonged therapy further necessitates the development of additional drugs for the treatment of hepatitis B virus (HBV) infections. We have evaluated a number of novel 2'-fluoro-2',3'-unsaturated D- and L-nucleosides for their anti-HBV activity in the HepG2-2.2.15 cell system. The most potent nucleosides were beta-L-2'-fluoro-2',3'-dideoxy-2',3'-didehydrocy-tidine (L-2'-Fd4C) and beta-L-2'-fluoro-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (L-2'-Fd4FC) with median effective concentrations (EC50) of 0.002 microM and 0.004 microM, respectively. The D-enantiomers of the 2'-fluoro-substituted cytidine analogues in this series showed activity, with the 5-fluorocytidine (D-2'-Fd4FC) being the most potent (EC50 = 0.05 microM). The active compounds were not cytotoxic to a number of cell lines or to bone marrow progenitor cells. Furthermore, mitochondrial DNA synthesis and function were not affected by these nucleosides. L-2'-Fd4C did not affect viral transcription, implying that it does not inhibit cellular RNA polymerase II. Studies with the HBV polymerase in core particles revealed that the 5'-triphosphates of L-2'-Fd4C and D-2'-Fd4FC produced a dose-dependent inhibition of the incorporation of 32P-dCTP into the HBV DNA, indicating that the mechanism of action of these compounds is through specific inhibition of viral DNA synthesis. This class of nucleosides, which exhibit potent antiviral activity and a favourable safety profile, have potential for the treatment of HBV infections and warrant further development.

Synthesis and anti-HCV activity of N9,5'-cyclo-3-(beta-D-ribofuranosyl)-8-azapurin-2-one derivatives.

A number of 1- or 6-substituted N9,5'-cyclo-3-(beta-ribofuranosyl)-8-azapurin-2-one derivatives were synthesized in multi-step reactions. Their anti-hepatitis C virus activities were evaluated and some structure-activity relationship is discussed.