Open AccessDiscovery of a Series of 2′-α-Fluoro,2′-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus
Author(s) -
Seema Mengshetti,
Longhu Zhou,
Ozkan Sari,
Coralie De Schutter,
Hongwang Zhang,
Jong Hyun Cho,
Sijia Tao,
Leda Bassit,
Kiran Verma,
Robert A. Domaoal,
Maryam Ehteshami,
Yong Jiang,
Reuben Ovadia,
Mahesh Kasthuri,
Olivia Russell,
Tamara R. McBrayer,
Tony Whitaker,
J. Pattassery,
Maria Luz G. Pascual,
Lothar Uher,
Biing Y. Lin,
Sam Lee,
Franck Amblard,
Steven J. Coats,
Raymond F. Schinazi
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b01300
Subject(s) - phosphoramidate , chemistry , hepatitis c virus , prodrug , nucleoside , polymerase , virology , virus , sofosbuvir , genotype , pharmacology , biochemistry , enzyme , biology , ribavirin , gene
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.