Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class

descriptionPublicationkeyboard_double_arrow_right Article 01 Sep 2020 English Publisher:Elsevier BVJournal:Bioorganic & Medicinal Chemistry Letters, volume 30, page 127,361 (issn: 0960-894X,

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Authors: Hiroshi, Nakamura; Shingo, Fujioka; Takashi, Terui; Satoshi, Okuda; Kentaro, Kondo; Yoshinori, Tamatani; Yusuke, Akagi; +6 Authors

doi: 10.1016/j.bmcl.2020.127361

pmid: 32738974

Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class

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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.

Related Organizations

Kanazawa University
Japan
Japan Tobacco (United States)
United States

Keywords

Genotype, Administration, Oral, Hepacivirus, Viral Nonstructural Proteins, Virus Replication, RNA-Dependent RNA Polymerase, Antiviral Agents, Hepatitis C, Structure-Activity Relationship, Pargyline, Pyrazines, Mutation, Humans

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