Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2

被引：183

作者：

Clark, Michael P. ^{[1
]}

Ledeboer, Mark W. ^{[1
]}

Davies, Ioana ^{[1
]}

Byrn, Randal A. ^{[1
]}

Jones, Steven M. ^{[1
]}

Perola, Emanuele ^{[1
]}

Tsai, Alice ^{[1
]}

Jacobs, Marc ^{[1
]}

Nti-Addae, Kwame ^{[1
]}

Bandarage, Upul K. ^{[1
]}

Boyd, Michael J. ^{[1
]}

Bethiel, Randy S. ^{[1
]}

Court, John J. ^{[1
]}

Deng, Hongbo ^{[1
]}

Duffy, John P. ^{[1
]}

Dorsch, Warren A. ^{[1
]}

Farmer, Luc J. ^{[2
]}

Gao, Huai ^{[1
]}

Gu, Wenxin ^{[1
]}

Jackson, Katrina ^{[1
]}

Jacobs, Dylan H. ^{[1
]}

Kennedy, Joseph M. ^{[1
]}

Ledford, Brian ^{[1
]}

Liang, Jianglin ^{[1
]}

Maltais, Francois ^{[1
]}

Murcko, Mark ^{[1
]}

Wang, Tiansheng ^{[1
]}

Wannamaker, M. Woods ^{[1
]}

Bennett, Hamilton B. ^{[1
]}

Leeman, Joshua R. ^{[1
]}

McNeil, Colleen ^{[1
]}

Taylor, William P. ^{[1
]}

Memmott, Christine ^{[1
]}

Jiang, Min ^{[1
]}

Rijnbrand, Rene ^{[1
]}

Bral, Christopher ^{[3
]}

Germann, Ursula ^{[1
]}

Nezami, Azin ^{[1
]}

Zhang, Yuegang ^{[1
]}

Salituro, Francesco G. ^{[4
]}

Bennani, Youssef L. ^{[2
]}

Charifson, Paul S. ^{[1
]}

机构：

[1] Vertex Pharmaceut Inc, Boston, MA 02210 USA

[2] Vertex Pharmaceut Canada Inc, Laval, PQ H7V 4A7, Canada

[3] Arrowhead Res Corp, Madison, WI 53711 USA

[4] Sage Therapeut, Cambridge, MA 02141 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 15期

关键词：

CAP-BINDING; POLYMERASE; SUBUNIT;

D O I：

10.1021/jm5007275

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C.; Leong, M. A.; Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

引用

页码：6668 / 6678

页数：11

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