2. Academic Validation
  3. Hepatitis C virus NS5A replication complex inhibitors. Part 6: Discovery of a novel and highly potent biarylimidazole chemotype with inhibitory activity toward genotypes 1a and 1b replicons

Hepatitis C virus NS5A replication complex inhibitors. Part 6: Discovery of a novel and highly potent biarylimidazole chemotype with inhibitory activity toward genotypes 1a and 1b replicons

  • J Med Chem. 2014 Mar 13;57(5):1995-2012. doi: 10.1021/jm4016203.
Makonen Belema 1,  Van N Nguyen,  Jeffrey L Romine,  Denis R St Laurent,  Omar D Lopez,  Jason T Goodrich,  Peter T Nower,  Donald R O'Boyle 2nd,  Julie A Lemm,  Robert A Fridell,  Min Gao,  Hua Fang,  Rudolph G Krause,  Ying-Kai Wang,  A Jayne Oliver,  Andrew C Good,  Jay O Knipe,  Nicholas A Meanwell,  Lawrence B Snyder
Affiliations

Affiliation

  • 1 Departments of Discovery Chemistry, ‡Virology, §Lead Discovery and Optimization, ∥Computer-Assisted Drug Design, and ⊥Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
PMID: 24437689 DOI: 10.1021/jm4016203
Abstract

A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained Antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-136267
    99.30%, HCV NS5A 抑制剂
    HCV
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