Abstract:
:Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2'-α-F-2'-β-C-methylcytidine 5'-triphosphate (8) was more potent than sofosbuvir's active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c-4e and 4m (EC50 = 0.19-0.25 μM) exhibited comparable potency to that of sofosbuvir (EC50 = 0.15 μM) on inhibition of wild-type replicons. Notably, 4c (EC50 = 0.366 μM) was 1.5-fold more potent than sofosbuvir (EC50 = 0.589 μM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c-4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Zhen L,Dai L,Wen X,Yao L,Jin X,Yang XW,Zhao W,Yu SQ,Yuan H,Wang G,Sun Hdoi
10.1021/acs.jmedchem.7b00262subject
Has Abstractpub_date
2017-07-27 00:00:00pages
6077-6088issue
14eissn
0022-2623issn
1520-4804journal_volume
60pub_type
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