Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection

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• 作者：Shanshan He ; Jingbo Xiao ; Andrés E. Dulcey ; Billy Lin ; Adam Rolt ; Zongyi Hu ; Xin Hu ; Amy Q. Wang ; Xin Xu ; Noel Southall ; Marc Ferrer ; Wei Zheng ; T. Jake Liang ; Juan J. Marugan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：841-853
• 全文大小：840K
• ISSN：1520-4804

文摘

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.