Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease

被引：5

作者：

Rudd, Michael T. ^{[1
]}

McCauley, John A. ^{[1
]}

Romano, Joseph J. ^{[1
]}

Butcher, John W. ^{[1
]}

Bush, Kimberly ^{[1
]}

McIntyre, Charles J. ^{[1
]}

Nguyen, Kevin T. ^{[1
]}

Gilbert, Kevin F. ^{[1
]}

Lyle, Terry A. ^{[1
]}

Holloway, M. Katharine ^{[4
]}

Wan, Bang-Lin ^{[3
]}

Vacca, Joseph P. ^{[1
]}

Summa, Vincenzo ^{[5
]}

Harper, Steven ^{[5
]}

Rowley, Michael ^{[5
]}

Carroll, Steven S. ^{[2
]}

Burlein, Christine ^{[2
]}

DiMuzio, Jillian M. ^{[2
]}

Gates, Adam ^{[2
]}

Graham, Donald J. ^{[2
]}

Huang, Qian ^{[2
]}

Ludmerer, Steven W. ^{[2
]}

McClain, Stephanie ^{[2
]}

McHale, Carolyn ^{[2
]}

Stahlhut, Mark ^{[2
]}

Fandozzi, Christine ^{[3
]}

Taylor, Anne ^{[3
]}

Trainor, Nicole ^{[3
]}

Olsen, David B. ^{[2
]}

Liverton, Nigel J. ^{[1
]}

机构：

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

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

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

[4] Merck Res Labs, Chem Modeling & Informat, West Point, PA 19486 USA

[5] Merck Res Labs, IRBM, Dept Med Chem, Rome, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 23期

关键词：

Hepatitis C; NS3/4A protease; Macrocycle; Alkoxyquinoline; P2-P4; linker; HEPATITIS-C VIRUS; PRECLINICAL PROFILE; DISCOVERY; REPLICATION; TMC435350; MK-5172;

D O I：

10.1016/j.bmcl.2012.08.106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：7201 / 7206

页数：6

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