一系列构象受限硫脲类似物作为新型丙型肝炎病毒抑制剂的合成、活性和药代动力学特性。

Synthesis, activity, and pharmacokinetic properties of a series of conformationally-restricted thiourea analogs as novel hepatitis C virus inhibitors.

机构信息

Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.

出版信息

Bioorg Med Chem. 2010 Sep 1;18(17):6414-21. doi: 10.1016/j.bmc.2010.07.002. Epub 2010 Jul 8.

DOI:10.1016/j.bmc.2010.07.002

PMID:20675142

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.

摘要

设计、合成并评价了一系列新型构象受限的硫脲类似物，以评估它们对 HCV 的抑制活性。本文报道了该类新硫脲化合物的合成、构效关系（SAR）和药代动力学特性。这些化合物在基于细胞的 HCV 亚基因组复制子检测中对 HCV 具有很强的抑制活性。在所测试的化合物中，芴类化合物 4b 表现出最强的活性（EC50=0.3μM），较低的细胞毒性（CC50＞50μM），与相应的芴酮化合物 4c 相比，具有显著更好的药代动力学特性。