MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

被引：195

作者：

Summa, Vincenzo ^{[1
]}

Ludmerer, Steven W. ^{[1
]}

McCauley, John A. ^{[1
]}

Fandozzi, Christine ^{[1
]}

Burlein, Christine ^{[1
]}

Claudio, Giuliano ^{[1
]}

Coleman, Paul J. ^{[1
]}

DiMuzio, Jillian M. ^{[1
]}

Ferrara, Marco ^{[1
]}

Di Filippo, Marcello ^{[1
]}

Gates, Adam T. ^{[1
]}

Graham, Donald J. ^{[1
]}

Harper, Steven ^{[1
]}

Hazuda, Darla J. ^{[1
]}

McHale, Carolyn ^{[1
]}

Monteagudo, Edith ^{[1
]}

Pucci, Vincenzo ^{[1
]}

Rowley, Michael ^{[1
]}

Rudd, Michael T. ^{[1
]}

Soriano, Aileen ^{[1
]}

Stahlhut, Mark W. ^{[1
]}

Vacca, Joseph P. ^{[1
]}

Olsen, David B. ^{[1
]}

Liverton, Nigel J. ^{[1
]}

Carroll, Steven S. ^{[1
]}

机构：

[1] Merck & Co Inc, Whitehouse Stn, NJ USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2012年 / 56卷 / 08期

关键词：

TREATMENT-NAIVE SUBJECTS; ANTIVIRAL ACTIVITY; MACROCYCLIC INHIBITORS; PEGINTERFERON ALPHA-2A; PRECLINICAL PROFILE; INITIAL TREATMENT; POTENT ACTIVITY; NS5A INHIBITOR; PLUS RIBAVIRIN; REPLICATION;

D O I：

10.1128/AAC.00324-12

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.

引用

页码：4161 / 4167

页数：7

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