Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)

被引：156

作者：

Seiwert, Scott D. ^{[1
]}

Andrews, Steven W. ^{[2
]}

Jiang, Yutong ^{[2
]}

Serebryany, Vladimir ^{[1
]}

Tan, Hua ^{[1
]}

Kossen, Karl ^{[1
]}

Rajagopalan, P. T. Ravi ^{[1
]}

Misialek, Shawn ^{[1
]}

Stevens, Sarah K. ^{[1
]}

Stoycheva, Antitsa ^{[1
]}

Hong, Jin ^{[1
]}

Lim, Sharlene R. ^{[1
]}

Qin, Xiaoli ^{[1
]}

Rieger, Robert ^{[2
]}

Condroski, Kevin R. ^{[2
]}

Zhang, Hailong ^{[2
]}

Do, Mary Geck ^{[2
]}

Lemieux, Christine ^{[2
]}

Hingorani, Gary P. ^{[2
]}

Hartley, Dylan P. ^{[2
]}

Josey, John A. ^{[2
]}

Pan, Lin ^{[1
]}

Beigelman, Leonid ^{[1
]}

Blatt, Lawrence M. ^{[1
]}

机构：

[1] InterMune Inc, Brisbane, CA 94005 USA

[2] Array Biopharma Inc, Boulder, CO 80301 USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2008年 / 52卷 / 12期

关键词：

D O I：

10.1128/AAC.00699-08

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Future treatments for chronic hepatitis C virus (HCV) infection are likely to include agents that target viral components directly. Here, the preclinical characteristics of ITMN-191, a peptidomimetic inhibitor of the NS3/4A protease of HCV, are described. ITMN-191 inhibited a reference genotype 1 NS3/4A protein in a time-dependent fashion, a hallmark of an inhibitor with a two-step binding mechanism and a low dissociation rate. Under preequilibrium conditions, 290 pM ITMN-191 half-maximally inhibited the reference NS3/4A protease, but a 35,000-fold-higher concentration did not appreciably inhibit a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Subnanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 4, 5, and 6, while single-digit nanomolar potency was observed against NS3/4A from genotypes 2b and 3a. Dilution of a preformed enzyme inhibitor complex indicated ITMN-191 remained bound to and inhibited NS3/4A for more than 5 h after its initial association. In cell-based potency assays, half-maximal reduction of genotype 1b HCV replicon RNA was afforded by 1.8 nM; 45 nM eliminated the HCV replicon from cells. Peginterferon alfa-2a displayed a significant degree of antiviral synergy with ITMN-191 and reduced the concentration of ITMN-191 required for HCV replicon elimination. A 30-mg/kg of body weight oral dose administered to rats or monkeys yielded liver concentrations 12 h after dosing that exceeded the ITMN-191 concentration required to eliminate replicon RNA from cells. These preclinical characteristics compare favorably to those of other inhibitors of NS3/4A in clinical development and therefore support the clinical investigation of ITMN-191 for the treatment of chronic hepatitis C.

引用

页码：4432 / 4441

页数：10

共 51 条

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