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

doi:10.1021/acs.jmedchem.5b00752

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 journal › Article › peer-review

19 Scopus citations

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 language	English (US)
Pages (from-to)	841-853
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	3
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00752
State	Published - Feb 11 2016
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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He, S., Xiao, J., Dulcey, A. E., Lin, B., Rolt, A., Hu, Z., Hu, X., Wang, A. Q., Xu, X., Southall, N., Ferrer, M., Zheng, W., Liang, T. J., & Marugan, J. J. (2016). Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection. Journal of Medicinal Chemistry, 59(3), 841-853. https://doi.org/10.1021/acs.jmedchem.5b00752

He, S, Xiao, J, Dulcey, AE, Lin, B, Rolt, A, Hu, Z, Hu, X, Wang, AQ, Xu, X, Southall, N, Ferrer, M, Zheng, W, Liang, TJ & Marugan, JJ 2016, 'Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection', Journal of Medicinal Chemistry, vol. 59, no. 3, pp. 841-853. https://doi.org/10.1021/acs.jmedchem.5b00752

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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.",

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doi = "10.1021/acs.jmedchem.5b00752",

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AU - He, Shanshan

AU - Xiao, Jingbo

AU - Dulcey, Andrés E.

AU - Lin, Billy

AU - Rolt, Adam

AU - Hu, Zongyi

AU - Hu, Xin

AU - Wang, Amy Q.

AU - Xu, Xin

AU - Southall, Noel

AU - Ferrer, Marc

AU - Zheng, Wei

AU - Liang, T. Jake

AU - Marugan, Juan J.

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AB - 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.

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

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