Design, Synthesis, and Biological Evaluation of 2-((4-Bisarylmethyl-piperazin-1-yl)methyl)benzonitrile Derivatives as HCV Entry Inhibitors,Journal of Medicinal Chemistry

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Design, Synthesis, and Biological Evaluation of 2-((4-Bisarylmethyl-piperazin-1-yl)methyl)benzonitrile Derivatives as HCV Entry Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-01-20 , DOI: 10.1021/acs.jmedchem.1c01637
Yixuan Wang ₁ , Jianrui Li _{1,

2} , Jiali Tan _{1,

2} , Bo Yang ₁ , Yanni Quan ₁ , Zonggen Peng _{1,

2} , Yanping Li ₁ , Zhuorong Li ₁

Affiliation

Viral entry inhibitors are absent in hepatitis C virus (HCV) treatment regimens although a dozen direct-acting antiviral (DAA) drugs are available now. Based on a previously identified HCV entry inhibitor L0909, chemical space exploration and structure–activity relationship (SAR) studies led to the discovery of a new derived scaffold 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile. Several new scaffold derivatives exhibited higher in vitro anti-HCV activity at low nanomolar concentrations compared to L0909. A biological study indicated that the high potency of active derivatives 3d, 3h, and 3i was primarily driven by the inhibitory effect on the virus entry stage. Moreover, an SPR experiment confirmed that this class of derivatives might target the HCV E1 protein. Pharmacokinetic studies indicated that compounds 3d and 3i are orally available and long-lasting in rat plasma after oral administration to rats by a single dose of 15 mg/kg. In conclusion, this work provided a novel 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile chemotype deserving further investigation into its antiviral therapeutic potential.

中文翻译：

2-((4-Bisarylmethyl-piperazin-1-yl)methyl)benzonitros 衍生物作为 HCV 进入抑制剂的设计、合成和生物学评价

尽管现在有十几种直接作用的抗病毒 (DAA) 药物可供使用，但丙型肝炎病毒 (HCV) 治疗方案中没有病毒进入抑制剂。基于先前确定的 HCV 进入抑制剂L0909，化学空间探索和构效关系 (SAR) 研究导致发现了一种新的衍生支架 2-((4-bisarylmethyl-pirapazin-1-yl)methyl)benzonitron。与L0909相比，几种新的支架衍生物在低纳摩尔浓度下表现出更高的体外抗 HCV 活性。一项生物学研究表明，活性衍生物3d、3h和3i的高效力主要是由于对病毒进入阶段的抑制作用。此外，SPR 实验证实，这类衍生物可能靶向 HCV E1 蛋白。药代动力学研究表明，化合物3d和3i在以 15 mg/kg 的单剂量对大鼠口服给药后，在大鼠血浆中可口服且持久。总之，这项工作提供了一种新的 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile 化学型，值得进一步研究其抗病毒治疗潜力。

更新日期：2022-02-10

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