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J Med Chem. 2017 Jul 27;60(14):6364-6383. doi: 10.1021/acs.jmedchem.7b00561. Epub 2017 Jul 13.

Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle.

Author information

1
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892-1800, United States.
2
University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States.
3
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Abstract

Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure-activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM. Lead compounds showed inhibition of the HCV pseudoparticle entry, suggesting a different mode of action from existing HCV drugs. Hit 7a and lead 7ii both showed synergistic effects in combination with existing HCV drugs. In vivo pharmacokinetics studies of 7ii showed high liver distribution and long half-life without obvious hepatotoxicity. The lead compounds are promising as preclinical candidates for the treatment of HCV infection and as molecular probes to study HCV pathogenesis.

PMID:
28636348
PMCID:
PMC6015499
DOI:
10.1021/acs.jmedchem.7b00561
[Indexed for MEDLINE]
Free PMC Article

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