2. Academic Validation
  3. 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

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

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.

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