Discovery of a Series of 2'-α-Fluoro,2'-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus

  • J Med Chem. 2019 Feb 28;62(4):1859-1874. doi: 10.1021/acs.jmedchem.8b01300.
Seema Mengshetti  1 ,  Longhu Zhou  1 ,  Ozkan Sari  1 ,  Coralie De Schutter  1 ,  Hongwang Zhang  1 ,  Jong Hyun Cho  1 ,  Sijia Tao  1 ,  Leda C Bassit  1 ,  Kiran Verma  1 ,  Robert A Domaoal  1 ,  Maryam Ehteshami  1 ,  Yong Jiang  1 ,  Reuben Ovadia  1 ,  Mahesh Kasthuri  1 ,  Olivia Ollinger Russell  1 ,  Tamara McBrayer  1 ,  Tony Whitaker  2 ,  Judy Pattassery  2 ,  Maria Luz Pascual  2 ,  Lothar Uher  2 ,  Biing Y Lin  2 ,  Sam Lee  2 ,  Franck Amblard  1 ,  Steven J Coats  1 ,  Raymond F Schinazi  1
Affiliations
  • 1. Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics , Emory University School of Medicine , Atlanta , Georgia 30322 , United States.
  • 2. Cocrystal Pharma, Inc. , Tucker , Georgia 30084 , United States.
PMID: 30653317 DOI: 10.1021/acs.jmedchem.8b01300
Abstract

Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B Polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.