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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)841-853
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number3
DOIs
StatePublished - Feb 11 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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