Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation

5 years ago

Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation

Xiaoliang Jin, Liang Dai, Haoliang Yuan, Hongbin Sun, Wenfeng Zhao, Xiao-Wen Yang, Lan Yao, Guangji Wang, Sheng-Qi Yu, Le Zhen, Xiaoan Wen

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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00262

DOI: 10.1021/acs.jmedchem.7b00262