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

• DOI: 10.1093/infdis/jiy039
• Publication Date: 2018-01-17T19:16:53Z
• Authors: Adam Rolt; Derek Le; Zongyi Hu; Amy Q Wang; Pranav Shah; Marc Singleton; Emma Hughes; Andrés E Dulcey; Shanshan He; Michio Imamura; Takuro Uchida; Kazuaki Chayama; Xin Xu; Juan J Marugan; T Jake Liang
• Keywords: Hepatitis C

Hepatitis C virus (HCV) is a small, single-stranded, positive-sense RNA 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 high costs there remains need for effective, shorter-duration, and affordable treatments. Recently, we disclosed activity of the cheap antihistamine chlorcyclizine, targeting viral entry. Following our hit-to-lead optimization campaign, report evaluation preclinical vitro absorption, distribution, metabolism, excretion properties, vivo pharmacokinetic profiles lead compounds. This led selection new compound efficacy chimeric mice engrafted primary human hepatocytes infected HCV. Further development incorporation this into DAA has potential improve treatment efficacy, affordability, accessibility.