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
| Autor: | Tamara R. McBrayer, Biing Y. Lin, Kiran Verma, Ozkan Sari, Olivia Ollinger Russell, Judy Pattassery, Yong Jiang, Maria Luz G. Pascual, Steven J. Coats, Seema Mengshetti, Leda Bassit, Jong Hyun Cho, Reuben Ovadia, Sijia Tao, Sam Lee, Mahesh Kasthuri, Robert A. Domaoal, Tony Whitaker, Coralie De Schutter, Raymond F. Schinazi, Longhu Zhou, Lothar Uher, Hongwang Zhang, Maryam Ehteshami, Franck Amblard |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Hepatitis C virus Deoxyribonucleosides Hepacivirus Viral Nonstructural Proteins medicine.disease_cause 01 natural sciences Antiviral Agents Article 03 medical and health sciences Dogs Pharmacokinetics Cell Line Tumor Drug Discovery medicine Animals Humans Prodrugs Enzyme Inhibitors Polymerase 030304 developmental biology 0303 health sciences biology Chemistry Drug discovery Phosphoramidate Prodrug 0104 chemical sciences 010404 medicinal & biomolecular chemistry Biochemistry Microsome biology.protein Microsomes Liver Molecular Medicine Deoxyuracil Nucleotides Nucleoside |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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