用于治疗丙型肝炎病毒感染的新型氯环利嗪衍生物的发现、优化及特性研究
Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection.
作者信息
He Shanshan, Xiao Jingbo, Dulcey Andrés E, Lin Billy, Rolt Adam, Hu Zongyi, Hu Xin, Wang Amy Q, Xu Xin, Southall Noel, Ferrer Marc, Zheng Wei, Liang T Jake, Marugan Juan J
机构信息
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 10 Center Drive, Bethesda, Maryland 20892, United States.
Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
出版信息
J Med Chem. 2016 Feb 11;59(3):841-53. doi: 10.1021/acs.jmedchem.5b00752. Epub 2016 Feb 1.
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.
最近，我们报道了氯环利嗪（CCZ，消旋体-2），一种非处方抗组胺哌嗪药物，在体外和体内均具有抗丙型肝炎病毒活性。在此，我们描述了结构-活性关系（SAR）研究工作，这些工作导致了新型氯环利嗪衍生物作为抗丙型肝炎病毒药物的优化。几种化合物对丙型肝炎病毒感染的EC50值低于10 nM，细胞毒性选择性指数高于2000，并显示出改善的体内药代动力学性质。优化后的分子可作为治疗丙型肝炎病毒感染的临床前先导候选药物，以及用于研究丙型肝炎病毒发病机制和宿主-病毒相互作用的探针。
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