2. Academic Validation
  3. 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

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

  • J Med Chem. 2019 May 9;62(9):4555-4570. doi: 10.1021/acs.jmedchem.9b00143.
Guangyi Wang 1,  Natalia Dyatkina 1,  Marija Prhavc 1,  Caroline Williams 1,  Vladimir Serebryany 1,  Yujian Hu 2,  Yongfei Huang 2,  Jinqiao Wan 2,  Xiangyang Wu 2,  Jerome Deval 1,  Amy Fung 1,  Zhinan Jin 1,  Hua Tan 1,  Kenneth Shaw 1,  Hyunsoon Kang 1,  Qingling Zhang 1,  Yuen Tam 1,  Antitsa Stoycheva 1,  Andreas Jekle 1,  David B Smith 1,  Leonid Beigelman 1
Affiliations

Affiliations

  • 1 Janssen BioPharma, Inc. , South San Francisco , California 94080 , United States.
  • 2 Department of Medicinal Chemistry , WuXi AppTec , Shanghai 200131 , P. R. China.
PMID: 30951311 DOI: 10.1021/acs.jmedchem.9b00143
Abstract

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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