title: New potent biaryl sulfate-based hepatitis C virus inhibitors.
abstract: The discovery of a new series of potent hepatitis C virus (HCV) NS5A inhibitors containing biaryl sulfone or sulfate cores is reported. Structure-activity relationship (SAR) studies on inhibitors containing various substitution patterns of the sulfate or sulfone core structure established that m-,m'- substituted biaryl sulfate core-based inhibitors containing an amide moiety (compound 20) or an imidazole moiety (compound 24) showed extremely high potency. Compound 20 demonstrated double-digit pM potencies against both genotype 1b (GT-1b) and 2a (GT-2a). Compound 24 also exhibited double-digit pM potencies against GT-1b and sub nM potencies against GT-2a. Furthermore, compounds 20 and 24 exhibited no cardiotoxicity in an hERG ligand binding assay and showed acceptable plasma stability and no mutagenic potential in the Ames test. In addition, these compounds showed distinctive additive effects in combination treatment with the NS5B targeting drug sofosbuvir (Sovaldi®). The results of this study showed that the compounds 20 and 24 could be effective HCV inhibitors.
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Youngsu
authors.initials: Y
authors.lastname: You
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Il Hak
authors.initials: IH
authors.lastname: Bae
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Seung Gi
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Min Hyeok
authors.initials: MH
authors.lastname: Jee
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea. Electronic address: sungkey@postech.ac.kr.
authors.forename: Sung Key
authors.initials: SK
authors.lastname: Jang
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea. Electronic address: kimbm@snu.ac.kr.
authors.forename: B Moon
authors.initials: BM
authors.lastname: Kim
mesh_terms: D000577:Amides / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D066126:Cardiotoxicity; D055808:Drug Discovery / Q000379:methods; D004347:Drug Interactions; D000072237:ERG1 Potassium Channel / Q000378:metabolism; D005838:Genotype; D016174:Hepacivirus / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000138:chemical synthesis / Q000494:pharmacology*; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000577:Amides; D000998:Antiviral Agents; D000072237:ERG1 Potassium Channel; D007093:Imidazoles; D013431:Sulfates; D013450:Sulfones; D017361:Viral Nonstructural Proteins; C000606913:KCNH2 protein, human; C029899:imidazole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Biaryl sulfate; HCV; NS5A inhibitor; Structure-activity relationship