Synthesis and Anti-HCV Activities of 4'-Fluoro-2'-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4'-Fluoro-2'- C-methyluridine 5'-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection.
Guangyi WangNatalia DyatkinaMarija PrhavcCaroline WilliamsVladimir SerebryanyYujian HuYongfei HuangJinqiao WanXiangyang WuJerome DevalAmy FungZhinan JinHua TanKenneth ShawHyunsoon KangQingling ZhangYuen TamAntitsa D StoychevaAndreas JekleDavid B SmithLeonid BeigelmanPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- hepatitis c virus
- molecular docking
- positron emission tomography
- human immunodeficiency virus
- photodynamic therapy
- induced apoptosis
- computed tomography
- endothelial cells
- high throughput
- small molecule
- cell cycle arrest
- liver injury
- cancer therapy
- pluripotent stem cells
- endoplasmic reticulum stress
- cell proliferation
- drug induced
- hiv infected
- cell death
- drug delivery
- light emitting