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

共 55 条

[1] Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3•4A protease inhibitors in treatment-naive subjects [J].

Bartels, Doug J. ;

Zhou, Yi ;

Zhang, Eileen Z. ;

Marcial, Michelle ;

Byrn, Randal A. ;

Pfeiffer, Thomas ;

Tigges, Ann M. ;

Adiwijaya, Bambang S. ;

Lin, Chao ;

Kwong, Ann D. ;

Kieffer, Tara L. .

JOURNAL OF INFECTIOUS DISEASES, 2008, 198 (06) :800-807

[2] Hepatitis C virus replication cycle [J].

Bartenschlager, Ralf ;

Cosset, Francois-Loic ;

Lohmann, Volker .

JOURNAL OF HEPATOLOGY, 2010, 53 (03) :583-585

[3]

Brainard DM, 2010, HEPATOLOGY, V52, p1216A

[4]

Brainard DM, 2010, HEPATOLOGY, V52, p706A

[5] BMS-650032, AN NS3 INHIBITOR, IN COMBINATION WITH PEGINTERFERON ALPHA-2A AND RIBAVIRIN IN TREATMENT-NAIVE SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION [J].

Bronowicki, J. -P. ;

Pol, S. ;

Thuluvath, P. J. ;

Larrey, D. ;

Martorell, C. T. ;

Rustgi, V. K. ;

Morris, D. W. ;

Younes, Z. ;

Fried, M. W. ;

Bourliere, M. ;

Hezode, C. ;

Massoud, O. ;

Abrams, G. A. ;

Ratziu, V. ;

Thiry, A. ;

Llamoso, C. ;

Hughes, E. A. ;

Hindes, R. G. .

JOURNAL OF HEPATOLOGY, 2011, 54 :S472-S472

[6] Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs [J].

Carroll, SS ;

Tomassini, JE ;

Bosserman, M ;

Getty, K ;

Stahlhut, MW ;

Eldrup, AB ;

Bhat, B ;

Hall, D ;

Simcoe, AL ;

LaFemina, R ;

Rutkowski, CA ;

Wolanski, B ;

Yang, ZC ;

Migliaccio, G ;

De Francesco, R ;

Kuo, LC ;

MacCoss, M ;

Olsen, DB .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (14) :11979-11984

[7] Robust Antiviral Efficacy upon Administration of a Nucleoside Analog to Hepatitis C Virus-Infected Chimpanzees [J].

Carroll, Steven S. ;

Ludmerer, Steven ;

Handt, Larry ;

Koeplinger, Kenneth ;

Zhang, Nanyan Rena ;

Graham, Donald ;

Davies, Mary-Ellen ;

MacCoss, Malcolm ;

Hazuda, Daria ;

Olsen, David B. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2009, 53 (03) :926-934

[8] ISOLATION OF A CDNA CLONE DERIVED FROM A BLOOD-BORNE NON-A, NON-B VIRAL-HEPATITIS GENOME [J].

CHOO, QL ;

KUO, G ;

WEINER, AJ ;

OVERBY, LR ;

BRADLEY, DW ;

HOUGHTON, M .

SCIENCE, 1989, 244 (4902) :359-362

[9] Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C [J].

Forestier, Nicole ;

Reesink, Hendrik W. ;

Weegink, Christine J. ;

McNair, Lindsay ;

Kieffer, Tara L. ;

Chu, Hui-May ;

Purdy, Susan ;

Jansen, Peter L. M. ;

Zeuzem, Stefan .

HEPATOLOGY, 2007, 46 (03) :640-648

[10]

Fried MW, 2010, HEPATOLOGY S, V4, pLB

← 1 2 3 4 5 6 →