title: Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection.
abstract: Recently, we reported that chlorcyclizine (CCZ, Rac-2), an over-the-counter antihistamine piperazine drug, possesses in vitro and in vivo activity against hepatitis C virus. Here, we describe structure-activity relationship (SAR) efforts that resulted in the optimization of novel chlorcyclizine derivatives as anti-HCV agents. Several compounds exhibited EC50 values below 10 nM against HCV infection, cytotoxicity selectivity indices above 2000, and showed improved in vivo pharmacokinetic properties. The optimized molecules can serve as lead preclinical candidates for the treatment of hepatitis C virus infection and as probes to study hepatitis C virus pathogenesis and host-virus interaction.
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: Shanshan
authors.initials: S
authors.lastname: He
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Dulcey
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: Billy
authors.initials: B
authors.lastname: Lin
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Rolt
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: Zongyi
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Amy Q
authors.initials: AQ
authors.lastname: Wang
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D010879:Piperazines; C084597:chlorcyclizine