New potent biaryl sulfate-based hepatitis C virus inhibitors

Title
New potent biaryl sulfate-based hepatitis C virus inhibitors
Authors
금교창유영수김희선배일학이승기지민혁장승기김병문
Keywords
HCV; NS5A inhibitor; Biaryl sulfate; Structure-activity relationship
Issue Date
2017-01
Publisher
European journal of medicinal chemistry
Citation
VOL 125-100
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.
URI
http://pubs.kist.re.kr/handle/201004/65263
ISSN
0223-5234
Appears in Collections:
KIST Publication > Article
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