2′-Chloro,2′-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture

5 years ago

2′-Chloro,2′-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture

Ozkan Sari, Leda Bassit, Longhu Zhou, Peng Liu, Tamara McBrayer, Ahmed Khalil, Robert A. Domaoal, Sijia Tao, Sawsan Mahmoud, Shaoman Zhou, Olivia Ollinger Russell, Maryam Ehteshami, Sheida Amiralaei, Steven J. Coats, Nageh Abou-Taleb, Tony Whitaker, Raymond F. Schinazi, Coralie De Schutter, Franck Amblard

Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2′-Cl,2′-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5′-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00067

DOI: 10.1021/acs.jmedchem.7b00067