Preclinical Pharmacological Development of Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection

An evaluation of preclinical in vitro ADME and in vivo pharmacokinetic profiles of several chlorcyclizine derivatives targeted towards HCV and in vivo efficacy in chimeric mice engrafted with primary human hepatocytes infected with HCV are reported. Abstract Hepatitis C virus (HCV) is a small, singl...

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Published in:The Journal of infectious diseases 2018-05, Vol.217 (11), p.1761-1769
Main Authors: Rolt, Adam, Le, Derek, Hu, Zongyi, Wang, Amy Q, Shah, Pranav, Singleton, Marc, Hughes, Emma, Dulcey, Andrés E, He, Shanshan, Imamura, Michio, Uchida, Takuro, Chayama, Kazuaki, Xu, Xin, Marugan, Juan J, Liang, T Jake
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - pharmacology
Carcinoma, Hepatocellular - virology
Cell Line
Genotype
Hepacivirus - drug effects
Hepatitis C, Chronic - drug therapy
Hepatocytes - virology
Humans
Liver Cirrhosis - virology
Liver Neoplasms - virology
Major and Brief Reports
Male
Mice
Mice, SCID
Piperazines - pharmacology
Virus Internalization - drug effects
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Summary:An evaluation of preclinical in vitro ADME and in vivo pharmacokinetic profiles of several chlorcyclizine derivatives targeted towards HCV and in vivo efficacy in chimeric mice engrafted with primary human hepatocytes infected with HCV are reported. Abstract Hepatitis C virus (HCV) is a small, single-stranded, positive-sense RNA virus that infects more than an estimated 70 million people worldwide. Untreated, persistent HCV infection often results in chronic hepatitis, cirrhosis, or liver failure, with progression to hepatocellular carcinoma. Current anti-HCV regimens comprising direct acting antivirals (DAAs) can provide curative treatment; however, due to high costs there remains a need for effective, shorter-duration, and affordable treatments. Recently, we disclosed anti-HCV activity of the cheap antihistamine chlorcyclizine, targeting viral entry. Following our hit-to-lead optimization campaign, we report evaluation of preclinical in vitro absorption, distribution, metabolism, and excretion properties, and in vivo pharmacokinetic profiles of lead compounds. This led to selection of a new lead compound and evaluation of efficacy in chimeric mice engrafted with primary human hepatocytes infected with HCV. Further development and incorporation of this compound into DAA regimens has the potential to improve treatment efficacy, affordability, and accessibility.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiy039