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

被引：12

作者：

Rolt, Adam ^{[1
]}

Le, Derek ^{[1
]}

Hu, Zongyi ^{[1
]}

Wang, Amy Q. ^{[2
]}

Shah, Pranav ^{[2
]}

Singleton, Marc ^{[2
]}

Hughes, Emma ^{[2
]}

Dulcey, Andres E. ^{[2
]}

He, Shanshan ^{[1
]}

Imamura, Michio ^{[3
]}

Uchida, Takuro ^{[3
]}

Chayama, Kazuaki ^{[3
]}

Xu, Xin ^{[2
]}

Marugan, Juan J. ^{[2
]}

Liang, T. Jake ^{[1
]}

机构：

[1] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA

[2] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA

[3] Hiroshima Univ, Grad Sch Biomed Sci, Dept Med & Mol Sci, Hiroshima, Japan

来源：

JOURNAL OF INFECTIOUS DISEASES | 2018年 / 217卷 / 11期

关键词：

antiviral; lead compound; drug development; pharmacokinetics; GENOTYPE; 1; INFECTION; ANTIVIRAL AGENTS; HCV; SOFOSBUVIR; THERAPIES; ASSAY; COMBINATION; LEDIPASVIR; VETERANS; SAFETY;

D O I：

10.1093/infdis/jiy039

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：1761 / 1769

页数：9