2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.,Journal of Medicinal Chemistry

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2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-07 , DOI: 10.1021/acs.jmedchem.0c00232
Xinbei Jiang ₁ , Jiali Tan ₁ , Yixuan Wang ₁ , Jinhua Chen ₁ , Jianrui Li _{1,

2} , Zhi Jiang ₁ , Yanni Quan ₁ , Jie Jin ₁ , Yuhuan Li _{1,

2} , Shan Cen ₁ , Yanping Li ₁ , Zonggen Peng _{1,

2} , Zhuorong Li ₁

Affiliation

Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC₅₀ = 0.022 μM, SI > 600), was identified by the structure–activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.

中文翻译：

2-（（4-Arylpiperazin-1-yl）methyl）苄腈衍生物作为口服丙型肝炎病毒抑制剂，具有新颖的作用机理。

尽管直接作用的抗病毒药物在过去十年中彻底改变了丙型肝炎病毒（HCV）的感染治疗方法，但在没有疫苗的情况下，需要更多的努力来消除HCV。4-（哌嗪-1-基）-2-（（对甲苯基氨基）甲基）-苯甲腈（1）是一种中等的HCV抑制剂，可通过使用HCV感染的Huh7.5细胞培养物进行的内部筛选确定。从其开始，化学优化提供了新的2-（（4-芳基哌嗪-1-基）甲基）苄腈支架，其对HCV的抗病毒活性显着提高。通过结构-活性关系研究确定了一种高效的HCV抑制剂35（L0909，EC ₅₀ = 0.022μM，SI> 600）。生物学研究表明，L0909可以通过在HCV进入阶段采取行动来阻止HCV复制。对于该化合物，观察到了对临床耐药HCV突变株的高敏感性以及与临床药物的协同作用。进一步的药物研究表明，L0909具有持久性，可以口服，并且体内毒性低。这些结果表明，L0909是有前途的HCV进入抑制剂，可用于单一或联合治疗。

更新日期：2020-05-07

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