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

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.

Fluoxazolevir inhibits hepatitis C virus infection in humanized chimeric mice by blocking viral membrane fusion

“…In summary, we show that fluoxazolevir inhibits HCV entry by blocking membrane fusion of viral endosomes, which is also the mechanism of action for other recently described entry inhibitors, such as chlorcyclizine, flunarizine and 4-aminoquinoline derivatives 46 – 48 . Our preclinical studies support fluoxazolevir as a promising candidate for the next generation of drug cocktails for HCV treatment.…”

“…The pharmacokinetic parameters were presented as mean ± standard error of the mean (SEM) for rats (n=3, plasma) and dogs (n=3). Pharmacokinetic parameters were derived using noncompartmental method with Phoenix WinNonLin, Version 6.2.0 (Certara, St. Louis, MO, USA) 46 .…”

A randomized, proof-of-concept clinical trial on repurposing chlorcyclizine for the treatment of chronic hepatitis C

“…Assessment of pharmacokinetics indicates that the plasma (S)-CCZ levels reached were in the range of 200 ng/mL. This is 2-fold over the EC 50 of (S)-CCZ against HCV genotype 2 (100 ng/mL), however, CCZ is much more active against HCV genotype 2 than the other genotypes (EC 50 in the range of 1-5 μg/mL) 15,16 . Because only one patient treated in this study was infected with genotype 2, these low plasma levels may account for sub-therapeutic effects of CCZ in these patients.…”

“…This study provides patient level data and an early framework for the development of new drugs with similarities to CCZ. Our recent structureactivity relationship campaign has generated several CCZ derivatives that are more potent and have more optimal pharmacokinetic features 15 . These improved compounds may be more suitable for further human testing and therapeutic development.…”

“…10 Various studies have reported drugs used for other purposes that have antiviral activity against various viral infections. [11][12][13][14][15] Recently, via high-throughput screening (HTS) of pharmaceutical collections, we and others discovered that the antihistamine chlorcyclizine HCl (CCZ) has anti-HCV activity. [16][17][18] CCZ is a first-generation over-the-counter piperazine class antihistamine that demonstrated high anti-HCV activity in vitro and in vivo with high liver distribution, synergy with various approved anti-HCV drugs and no evidence of drug resistance.…”