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

J Med Chem. 2017 Jul 13;60(13):5424-5437. doi: 10.1021/acs.jmedchem.7b00067.

Shaoman Zhou ¹, Sawsan Mahmoud ¹ ², Peng Liu ¹, Longhu Zhou ¹, Maryam Ehteshami ¹, Leda Bassit ¹, Sijia Tao ¹, Robert A Domaoal ¹, Ozkan Sari ¹, Coralie De Schutter ¹, Sheida Amiralaei ¹, Ahmed Khalil ¹, Olivia Ollinger Russell ¹, Tamara McBrayer ³, Tony Whitaker ³, Nageh Abou-Taleb ², Franck Amblard ¹, Steven J Coats ³, Raymond F Schinazi ¹

Affiliations

1 Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia 30307, United States.
2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University , Helwan, Egypt.
3 Cocrystal Pharma, Inc., Tucker, Georgia 30084, United States.

PMID: 28595015 DOI: 10.1021/acs.jmedchem.7b00067

Abstract

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.

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