Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis CNS3/4A protease

被引：99

作者：

Liverton, Nigel J. ^{[1
]}

Holloway, M. Katharine ^{[4
]}

McCauley, John A. ^{[1
]}

Rudd, Michael T. ^{[1
]}

Butcher, John W. ^{[1
]}

Carroll, Steven S. ^{[2
]}

DiMuzio, Jillian ^{[2
]}

Fandozzi, Christine ^{[3
]}

Gilbert, Kevin F. ^{[1
]}

Mao, Shi-Shan ^{[2
]}

Mclntyre, Charles J. ^{[1
]}

Nguyen, Kevin T. ^{[1
]}

Romano, Joseph J. ^{[1
]}

Stahlhut, Mark ^{[2
]}

Wan, Bang-Lin ^{[3
]}

Olsen, David B. ^{[2
]}

Vacca, Joseph P. ^{[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, Dept Mol Syst, West Point, PA 19486 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2008年 / 130卷 / 14期

关键词：

D O I：

10.1021/ja711120r

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.

引用

页码：4607 / +

页数：4

共 22 条

[1] Synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) derivatives:: Key intermediates for the preparation of inhibitors of the hepatitis C virus NS3 protease [J].

Beaulieu, PL ;

Gillard, J ;

Bailey, MD ;

Boucher, C ;

Duceppe, JS ;

Simoneau, B ;

Wang, XJ ;

Zhang, L ;

Grozinger, K ;

Houpis, I ;

Farina, V ;

Heimroth, H ;

Krueger, T ;

Schnaubelt, J .

JOURNAL OF ORGANIC CHEMISTRY, 2005, 70 (15) :5869-5879

[2] Hepatitis C and liver transplantation [J].

Brown, RS .

NATURE, 2005, 436 (7053) :973-978

[3] Potent 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid-based macrocyclic inhibitors of hepatitis C virus NS3 protease [J].

Chen, KX ;

Njoroge, FG ;

Pichardo, J ;

Prongay, A ;

Butkiewicz, N ;

Yao, N ;

Madison, V ;

Girijavallabhan, V .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (02) :567-574

[4] Discovery of small-molecule inhibitors of HCVNS3-4A protease as potential therapeutic agents against HCV infection [J].

Chen, SH ;

Tan, SL .

CURRENT MEDICINAL CHEMISTRY, 2005, 12 (20) :2317-2342

[5] Control of hepatitis C: A medicinal chemistry perspective [J].

Gordon, CP ;

Keller, PA .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (01) :1-20

[6] An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus [J].

Lamarre, D ;

Anderson, PC ;

Bailey, M ;

Beaulieu, P ;

Bolger, G ;

Bonneau, P ;

Bös, M ;

Cameron, DR ;

Cartier, M ;

Cordingley, MG ;

Faucher, AM ;

Goudreau, N ;

Kawai, SH ;

Kukolj, G ;

Lagacé, L ;

LaPlante, SR ;

Narjes, H ;

Poupart, MA ;

Rancourt, J ;

Sentjens, RE ;

St George, R ;

Simoneau, B ;

Steinmann, G ;

Thibeault, D ;

Tsantrizos, YS ;

Weldon, SM ;

Yong, CL ;

Llinàs-Brunet, M .

NATURE, 2003, 426 (6963) :186-189

[7]

LaPlante Steven R., 2005, Current Medicinal Chemistry - Anti-Infective Agents, V4, P111, DOI 10.2174/1568012053507016

[8] Pathogenesis of hepatitis C-associated hepatocellular carcinoma [J].

Liang, TJ ;

Heller, T .

GASTROENTEROLOGY, 2004, 127 (05) :S62-S71

[9]

Lin C., 2006, Infectious Disorders - Drug Targets, V6, P3, DOI 10.2174/187152606776056706

[10] Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061 [J].

Llinàs-Brunet, M ;

Bailey, MD ;

Bolger, G ;

Brochu, C ;

Faucher, AM ;

Ferland, JM ;

Garneau, M ;

Ghiro, E ;

Gorys, V ;

Grand-Maître, C ;

Halmos, T ;

Lapeyre-Paquette, N ;

Liard, F ;

Poirier, M ;

Rhéaume, M ;

Tsantrizos, YS ;

Lamarre, D .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (07) :1605-1608

← 1 2 3 →