Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

被引：133

作者：

McCauley, John A. ^{[1
]}

McIntyre, Charles J. ^{[1
]}

Rudd, Michael T. ^{[1
]}

Nguyen, Kevin T. ^{[1
]}

Romano, Joseph J. ^{[1
]}

Butcher, John W. ^{[1
]}

Gilbert, Kevin F. ^{[1
]}

Bush, Kimberly J. ^{[1
]}

Holloway, M. Katharine ^{[2
]}

Swestock, John ^{[1
]}

Wan, Bang-Lin ^{[1
]}

Carroll, Steven S. ^{[3
]}

DiMuzio, Jillian M. ^{[3
]}

Graham, Donald J. ^{[3
]}

Ludmerer, Steven W. ^{[3
]}

Mao, Shi-Shan ^{[3
]}

Stahlhut, Mark W. ^{[3
]}

Fandozzi, Christine M. ^{[4
]}

Trainor, Nicole ^{[4
]}

Olsen, David B. ^{[3
]}

Vacca, Joseph P. ^{[1
]}

Liverton, Nigel J. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Antiviral Res, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 06期

关键词：

OLEFIN-METATHESIS CATALYSTS; RING-CLOSING METATHESIS; PRECLINICAL PROFILE; INITIAL TREATMENT; IN-VITRO; POTENT; SCH-503034; RIBAVIRIN; EFFICIENT; INTERFERON-ALPHA-2B;

D O I：

10.1021/jm9015526

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of H CV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the PI side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral closing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

引用

页码：2443 / 2463

页数：21

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