Synthesis, activity, and pharmacokinetic properties of a series of conformationally-restricted thiourea analogs as novel hepatitis C virus inhibitors.
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.
Kang
Iou-Jiun
IJ
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Wang
Li-Wen
LW
Yeh
Teng-Kuang
TK
Lee
Chung-Chi
CC
Lee
Yen-Chun
YC
Hsu
Sheng-Ju
SJ
Wu
Yen-Shian
YS
Wang
Jing-Chyi
JC
Chao
Yu-Sheng
YS
Yueh
Andrew
A
Chern
Jyh-Haur
JH
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*
D000998:Antiviral Agents; D005449:Fluorenes; D013890:Thiourea