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Updated: Dec 13, 2025

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class
Hiroshi Nakamura1, Shingo Fujioka2, Takashi Terui2
1Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan; Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Abstract:
A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.
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