Journal of Medicinal Chemistry p. 4555 - 4570 (2019)
Update date:2022-08-15
Topics:
Wang, Guangyi
Dyatkina, Natalia
Prhavc, Marija
Williams, Caroline
Serebryany, Vladimir
Hu, Yujian
Huang, Yongfei
Wan, Jinqiao
Wu, Xiangyang
Deval, Jerome
Fung, Amy
Jin, Zhinan
Tan, Hua
Shaw, Kenneth
Kang, Hyunsoon
Zhang, Qingling
Tam, Yuen
Stoycheva, Antitsa
Jekle, Andreas
Smith, David B.
Beigelman, Leonid
We report the synthesis and biological evaluation of a series of 4′-fluoro-2′-C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.
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