- Allosteric N-acetamide-indole-6-carboxylic acid thumb pocket 1 inhibitors of hepatitis C virus NS5B polymerase-Acylsulfonamides and acylsulfamides as carboxylic acid replacements
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Acylsulfonamide and acylsulfamide as surrogates for the carboxylic acid function of N-acetamide-indole-6-carboxylic acids were evaluated as allosteric inhibitors of hepatitis C virus (HCV) NS5B polymerase. Several analogs displayed excellent antiviral pot
- Beaulieu, Pierre L.,Coulombe, Rene,Gillard, James,Brochu, Christian,Duan, Jianmin,Garneau, Michel,Jolicoeur, Eric,Kuhn, Peter,Poupart, Marc-Andre,Rancourt, Jean,Stammers, Timothy A.,Thavonekham, Bounkham,Kukolj, George
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- Finger-loop inhibitors of the HCV NS5b polymerase. Part 1: Discovery and optimization of novel 1,6- and 2,6-macrocyclic indole series
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Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile.
- McGowan, David,Vendeville, Sandrine,Lin, Tse-I,Tahri, Abdellah,Hu, Lili,Cummings, Maxwell D.,Amssoms, Katie,Berke, Jan Martin,Canard, Maxime,Cleiren, Erna,Dehertogh, Pascale,Last, Stefaan,Fransen, Els,Van Der Helm, Elisabeth,Van Den Steen, Iris,Vijgen, Leen,Rouan, Marie-Claude,Fanning, Gregory,Nyanguile, Origène,Van Emelen, Kristof,Simmen, Kenneth,Raboisson, Pierre
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scheme or table
p. 4431 - 4436
(2012/09/07)
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- MACROCYCLIC INDOLES AS HEPATITIS C VIRUS INHIBITORS
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The present invention relates to inhibitors of HCV replication of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, formula (I), wherein R1; R3; and R4 have the meaning defined in the claims. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.
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Page/Page column 57-58
(2009/07/25)
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- Development of carboxylic acid replacements in indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase
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Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here 2 series of indole-N-acetamides, bearing
- Stansfield, Ian,Pompei, Marco,Conte, Immacolata,Ercolani, Caterina,Migliaccio, Giovanni,Jairaj, Mark,Giuliano, Claudio,Rowley, Michael,Narjes, Frank
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p. 5143 - 5149
(2008/02/12)
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- Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: From benzimidazole to indole scaffolds
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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 ~ 50 nM).
- Beaulieu, Pierre L.,Gillard, James,Bykowski, Darren,Brochu, Christian,Dansereau, Nathalie,Duceppe, Jean-Simon,Hache, Bruno,Jakalian, Araz,Lagace, Lisette,LaPlante, Steven,McKercher, Ginette,Moreau, Elaine,Perreault, Stephane,Stammers, Timothy,Thauvette, Louise,Warrington, Jeff,Kukolj, George
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p. 4987 - 4993
(2007/10/03)
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- Potent inhibitors of subgenomic hepatitis C virus RNA replication through optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B polymerase
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Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. Compounds that block replication of subgenomic HCV RNA in liver cells are of interest because of their demonstrated antivir
- Harper, Steven,Avolio, Salvatore,Pacini, Barbara,Di Filippo, Marcello,Altamura, Sergio,Tomei, Licia,Paonessa, Giacomo,Di Marco, Stefania,Carfi, Andrea,Giuliano, Claudio,Padron, Julio,Bonelli, Fabio,Migliaccio, Giovanni,De Francesco, Raffaele,Laufer, Ralph,Rowley, Michael,Narjes, Frank
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p. 4547 - 4557
(2007/10/03)
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- Inhibitors of HCV replication
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Compounds having the structure of formula (I) are disclosed. The compounds can inhibit hepatitis C virus (HCV) replication, and in particular the function of the HCV NS5B protein.
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Page/Page column 8
(2010/02/11)
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- VIRAL POLYMERASE INHIBITORS
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An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein wherein A, B, R2, R3, L, M1, M2, M3, M4, Y1, Y0, Z and Sp are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.
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- Viral polymerase inhibitors
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An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: wherein: A is O, S, NR1, or CR1, wherein R1 is defined herein; ---- represents either a single or a double bond; R2 is selected from: H, halogen, R21, OR21, SR21, COOR21, SO2N(R22)2, N(R22)2, CON(R22)2, NR22C(O)R22 or NR22C(O)NR22 wherein R21 and each R22 is defined herein; B is NR3 or CR3, with the proviso that one of A or B is either CR1 or CR3, wherein R3 is defined herein; K is N or CR4, wherein R4 is defined herein; L is N or CR5, wherein R5 has the same definition as R4 defined above; M is N or CR7, wherein R7 has the same definition as R4 defined above; Y1 is O or S; Z is N(R6a)R6 or OR6, wherein R6a is H or alkyl or NR61R62 wherein R61 and R62 are defined herein; a salt or a derivative thereof, as an inhibitor of HCV NS5B polymerase.
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