title: Synthesis, activity, and pharmacokinetic properties of a series of conformationally-restricted thiourea analogs as novel hepatitis C virus inhibitors.
abstract: A series of novel conformationally-restricted thiourea analogs were designed, synthesized, and evaluated for their anti-HCV activity. Herein we report the synthesis, structure-activity relationships (SARs), and pharmacokinetic properties of this new class of thiourea compounds that showed potent inhibitory activities against HCV in the cell-based subgenomic HCV replicon assay. Among compounds tested, the fluorene compound 4b was found to possess the most potent activity (EC(50)=0.3 microM), lower cytotoxicity (CC(50)>50 microM), and significantly better pharmacokinetic properties compared to its corresponding fluorenone compound 4c.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Iou-Jiun
authors.initials: IJ
authors.lastname: Kang
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Wang
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Lee
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lee
authors.forename: Sheng-Ju
authors.initials: SJ
authors.lastname: Hsu
authors.forename: Yen-Shian
authors.initials: YS
authors.lastname: Wu
authors.forename: Jing-Chyi
authors.initials: JC
authors.lastname: Wang
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Andrew
authors.initials: A
authors.lastname: Yueh
authors.forename: Jyh-Haur
authors.initials: JH
authors.lastname: Chern
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005449:Fluorenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D005449:Fluorenes; D013890:Thiourea