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.