Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection.

Therapeutic Approaches

Abstract

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.

Authors

He, Shanshan; Xiao, Jingbo; Dulcey, Andrés E; Lin, Billy; Rolt, Adam; Hu, Zongyi; Hu, Xin; Wang, Amy; Xu, Xin; Southall, Noel; Ferrer-Alegre, Marc; Zheng, Wei; Liang, T Jake; Marugan, Juan;

Keywords

  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Hepacivirus/ drug effects
  • Hepatitis C/ drug therapy
  • Hepatitis C/ virology
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Piperazines/ chemical synthesis
  • Piperazines/ chemistry
  • Piperazines/ therapeutic use
  • Structure-Activity Relationship

External Links