N-Acetamideindolecarboxylic acid allosteric 'finger-loop' inhibitors of the hepatitis C virus NS5B polymerase: discovery and initial optimization studies

被引：19

作者：

Beaulieu, Pierre L. ^{[1
]}

Jolicoeur, Eric ^{[1
]}

Gillard, James ^{[1
]}

Brochu, Christian ^{[1
]}

Coulombe, Rene ^{[1
]}

Dansereau, Nathalie ^{[2
]}

Duan, Jianmin ^{[2
]}

Garneau, Michel ^{[2
]}

Jakalian, Araz ^{[1
]}

Kuehn, Peter ^{[1
]}

Lagace, Lisette ^{[2
]}

LaPlante, Steven ^{[1
]}

McKercher, Ginette ^{[2
]}

Perrault, Stephane ^{[1
]}

Poirier, Martin ^{[1
]}

Poupart, Marc-Andre ^{[1
]}

Stammers, Timothy ^{[1
]}

Thauvette, Louise ^{[2
]}

Thavonekham, Bounkham ^{[1
]}

Kukolj, George ^{[1
]}

机构：

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

[2] Boehringer Ingelheim Canada Ltd, Dept Biol Sci, Res & Dev, Laval, PQ H7S 2G5, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 03期

关键词：

HCV NS5B polymerase; HCV replicon inhibitors; Allosteric inhibitors; Antivirals; Hepatitis C virus; BENZIMIDAZOLE DERIVATIVES; NONNUCLEOSIDE INHIBITORS; INFECTION; POTENT;

D O I：

10.1016/j.bmcl.2009.12.101

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR studies at the N(1)-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC(50) <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：857 / 861

页数：5

共 15 条

[1] Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCVNS5B polymerase:: From benzimidazole to indole scaffolds
Beaulieu, Pierre L.
Gillard, James
Bykowski, Darren
Brochu, Christian
Dansereau, Nathalie
Duceppe, Jean-Simon
Haché, Bruno
Jakalian, Araz
Lagacé, Lisette
LaPlante, Steven
McKercher, Ginette
Moreau, Elaine
Perreault, Stphane
Stammers, Timothy
Thauvette, Louise
Warrington, Jeff
Kukolj, George
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (19) : 4987 - 4993
[2] Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection
Beaulieu, Pierre L.
[J]. EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (02) : 145 - 164
[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
Beaulieu, PL
Bousquet, Y
Gauthier, J
Gillard, J
Marquis, M
McKercher, G
Pellerin, C
Valois, S
Kukolj, G
[J]. 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
Beaulieu, PL
Bös, M
Bousquet, Y
DeRoy, P
Fazal, G
Gauthier, J
Gillard, J
Goulet, S
McKercher, G
Poupart, MA
Valois, S
Kukolj, G
[J]. 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
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
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) : 119 - 124
[6] BEAULIEU PL, 2004, Patent No. 04065367
[7] Brown NA, 2009, EXPERT OPIN INV DRUG, V18, P709, DOI [10.1517/13543780902854194 , 10.1517/13543780902854194]
[8] Preclinical pharmacokinetics and metabolism of a potent non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase
Giuliano, C
Fiore, F
Di Marco, A
Velazquez, JP
Bishop, A
Bonelli, F
Gonzalez-Paz, O
Marcucci, I
Harper, S
Narjes, F
Pacini, B
Monteagudo, E
Migliaccio, G
Rowley, M
Laufer, R
[J]. XENOBIOTICA, 2005, 35 (10-11) : 1035 - 1054
[9] Potent inhibitors of subgenomic hepatitis C virus RNA replication through optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B polymerase
Harper, S
Avolio, S
Pacini, B
Di Filippo, M
Altamura, S
Tomei, L
Paonessa, G
Di Marco, S
Carfi, A
Giuliano, C
Padron, J
Bonelli, F
Migliaccio, G
De Francesco, R
Laufer, R
Rowley, M
Narjes, F
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (14) : 4547 - 4557
[10] Development and preliminary optimization of indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase
Harper, S
Pacini, B
Avolio, S
Di Filippo, M
Migliaccio, G
Laufer, R
De Francesco, R
Rowley, M
Narjes, F
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (05) : 1314 - 1317

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