| Autor: |
Mengshetti, Seema, Zhou, Longhu, Sari, Ozkan, De Schutter, Coralie, Zhang, Hongwang, Cho, Jong Hyun, Tao, Sijia, Bassit, Leda C., Verma, Kiran, Domaoal, Robert A., Ehteshami, Maryam, Jiang, Yong, Ovadia, Reuben, Kasthuri, Mahesh, Ollinger Russell, Olivia, McBrayer, Tamara, Whitaker, Tony, Pattassery, Judy, Pascual, Maria Luz, Uher, Lothar, Lin, Biing Y., Lee, Sam, Amblard, Franck, Coats, Steven J., Schinazi, Raymond F. |
| Zdroj: |
Journal of Medicinal Chemistry; January 2019, Vol. 62 Issue: 4 p1859-1874, 16p |
| Abstrakt: |
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 27and 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 28is superior to 27and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent. |
| Databáze: |
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