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
  • 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.