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

Therapeutic Approaches

Abstract

Hepatitis C virus (HCV) is a small, single-stranded, positive sense RNA virus that infects more than an estimated 70 million people worldwide. Left untreated, persistent infection of HCV often results in chronic hepatitis, cirrhosis or liver failure with progression to hepatocellular carcinoma. Current anti-HCV regimens comprising direct acting antivirals (DAAs) can now provide curative treatment, however the high cost of these therapies limit their access and impact in some of the most at-risk populations, there remains an unmet therapeutic need for effective, shorter-duration and affordable treatment options. Recently, we disclosed the anti-HCV activity of the cheap, over-the-counter antihistamine chlorcyclizine targeting viral entry. Following our hit-to-lead optimization campaign, here we report an evaluation of preclinical in vitro ADME and in vivo pharmacokinetic profiles of several lead compounds, which 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 lead compound into existing DAA regimens has the potential to improve efficacy, affordability and accessibility of treatment.

Authors

Rolt, Adam; Le, Derek; Hu, Zongyi; Wang, Amy; Shah, Pranav; Singleton, Marc; Hughes, Emma; Dulcey, Andrés E; He, Shanshan; Imamura, Michio; Uchida, Takuro; Chayama, Kazuaki; Xu, Xin; Marugan, Juan; Liang, T Jake;

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