Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 13, Pages 5424-5437Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00067
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Funding
- NIH [5P30-AI-50409]
- Egyptian Ministry of Higher Education
- Egyptian Educational Culture Bureau in USA
- Ph.D. thesis committee
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Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a beta-D-2'-Cl,2 '-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NSSB polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
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