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

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

  • J Med Chem. 2020 Jun 11;63(11):5972-5989. 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
Affiliations

Affiliations

  • 1 CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Abstract

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.

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