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Eur J Med Chem. 2017 Jan 5;125:87-100. doi: 10.1016/j.ejmech.2016.09.031. Epub 2016 Sep 10.

New potent biaryl sulfate-based hepatitis C virus inhibitors.

Author information

1
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
2
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea.
3
Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
4
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.
5
Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea. Electronic address: sungkey@postech.ac.kr.
6
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea. Electronic address: kimbm@snu.ac.kr.

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.

KEYWORDS:

Biaryl sulfate; HCV; NS5A inhibitor; Structure-activity relationship

PMID:
27657807
DOI:
10.1016/j.ejmech.2016.09.031
[Indexed for MEDLINE]

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