Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCVNS5B polymerase:: From benzimidazole to indole scaffolds

被引：70

作者：

Beaulieu, Pierre L. ^{[1
]}

Gillard, James ^{[1
]}

Bykowski, Darren ^{[1
]}

Brochu, Christian ^{[1
]}

Dansereau, Nathalie ^{[1
]}

Duceppe, Jean-Simon ^{[1
]}

Haché, Bruno ^{[1
]}

Jakalian, Araz ^{[1
]}

Lagacé, Lisette ^{[1
]}

LaPlante, Steven ^{[1
]}

McKercher, Ginette ^{[1
]}

Moreau, Elaine ^{[1
]}

Perreault, Stphane ^{[1
]}

Stammers, Timothy ^{[1
]}

Thauvette, Louise ^{[1
]}

Warrington, Jeff ^{[1
]}

Kukolj, George ^{[1
]}

机构：

[1] Boehringer Ingelheim Canada Ltd, Res & Dev, Laval, PQ H7S 2G5, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 19期

关键词：

HCVNS5B polymerase; hepatitis C virus; allosteric inhibitors; replicon; antiviral; indoles;

D O I：

10.1016/j.bmcl.2006.07.074

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC50 similar to 50 nM). (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：4987 / 4993

页数：7

共 23 条

[1]

Beaulieu P. L., 2003, Int. Patent Appl., Patent No. [WO 03010140, 03010140]

[2]

Beaulieu Pierre L, 2004, Curr Opin Investig Drugs, V5, P838

[3] Non-nucleoside benzimidazole-based allosteric inhibitors of the hepatitis C virus NS5B polymerase: Inhibition of subgenomic hepatitis C virus RNA replicons in Huh-7 cells [J].

Beaulieu, PL ;

Bousquet, Y ;

Gauthier, J ;

Gillard, J ;

Marquis, M ;

McKercher, G ;

Pellerin, C ;

Valois, S ;

Kukolj, G .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (27) :6884-6892

[4] Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase:: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency [J].

Beaulieu, PL ;

Bös, M ;

Bousquet, Y ;

DeRoy, P ;

Fazal, G ;

Gauthier, J ;

Gillard, J ;

Goulet, S ;

McKercher, G ;

Poupart, MA ;

Valois, S ;

Kukolj, G .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (04) :967-971

[5] Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase:: discovery and preliminary SAR of benzimidazole derivatives [J].

Beaulieu, PL ;

Bös, M ;

Bousquet, Y ;

Fazal, G ;

Gauthier, J ;

Gillard, J ;

Goulet, S ;

LaPlante, S ;

Poupart, MA ;

Lefebvre, S ;

McKercher, G ;

Pellerin, C ;

Austel, V ;

Kukolj, G .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) :119-124

[6]

Coulombe R., 2004, Patent Application, Patent No. [WO-04/099241, 04099241]

[7] Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site [J].

Di Marco, S ;

Volpari, C ;

Tomei, L ;

Altamura, S ;

Harper, S ;

Narjes, F ;

Koch, U ;

Rowley, M ;

De Francesco, R ;

Migliaccio, G ;

Carfí, A .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (33) :29765-29770

[8] GENERAL METHOD FOR SYNTHESIS OF INDOLES [J].

GASSMAN, PG ;

VANBERGE.TJ ;

GILBERT, DP ;

CUE, BW .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1974, 96 (17) :5495-5508

[9] The therapeutic potential of NS3 protease inhibitors in HCV infection [J].

Goudreau, N ;

Llinàs-Brunet, M .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2005, 14 (09) :1129-1144

[10] Development and preliminary optimization of indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase [J].

Harper, S ;

Pacini, B ;

Avolio, S ;

Di Filippo, M ;

Migliaccio, G ;

Laufer, R ;

De Francesco, R ;

Rowley, M ;

Narjes, F .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (05) :1314-1317

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