Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase
[Display omitted] The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-09, Vol.26 (18), p.4536-4541 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Pierra Rouvière, Claire Amador, Agnès Badaroux, Eric Convard, Thierry Da Costa, Daniel Dukhan, David Griffe, Ludovic Griffon, Jean-François LaColla, Massimiliano Leroy, Frédéric Liuzzi, Michel Loi, Anna Giulia McCarville, Joe Mascia, Valeria Milhau, Julien Onidi, Loredana Paparin, Jean-Laurent Rahali, Rachid Sais, Efisio Seifer, Maria Surleraux, Dominique Standring, David Dousson, Cyril |
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The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study. |
| doi_str_mv | 10.1016/j.bmcl.2016.01.042 |
| format | Article |
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The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.01.042</identifier><identifier>PMID: 27520942</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Allosteric inhibitors ; Allosteric Site ; Amide bioisostere ; Antiviral Agents - chemistry ; Antiviral Agents - metabolism ; Antiviral Agents - pharmacology ; Crystallography, X-Ray ; Direct-acting antivirals ; Genotype ; Hepacivirus - drug effects ; Hepatitis C virus ; NS5B non-nucleoside inhibitors ; Polymerase inhibitors ; Structure-Activity Relationship ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-09, Vol.26 (18), p.4536-4541</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-4658327eb2600ed7da57bddf039ec043eeb1e69fb420ba2b1c4f99faa630520f3</citedby><cites>FETCH-LOGICAL-c389t-4658327eb2600ed7da57bddf039ec043eeb1e69fb420ba2b1c4f99faa630520f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X16300427$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27520942$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pierra Rouvière, Claire</creatorcontrib><creatorcontrib>Amador, Agnès</creatorcontrib><creatorcontrib>Badaroux, Eric</creatorcontrib><creatorcontrib>Convard, Thierry</creatorcontrib><creatorcontrib>Da Costa, Daniel</creatorcontrib><creatorcontrib>Dukhan, David</creatorcontrib><creatorcontrib>Griffe, Ludovic</creatorcontrib><creatorcontrib>Griffon, Jean-François</creatorcontrib><creatorcontrib>LaColla, Massimiliano</creatorcontrib><creatorcontrib>Leroy, Frédéric</creatorcontrib><creatorcontrib>Liuzzi, Michel</creatorcontrib><creatorcontrib>Loi, Anna Giulia</creatorcontrib><creatorcontrib>McCarville, Joe</creatorcontrib><creatorcontrib>Mascia, Valeria</creatorcontrib><creatorcontrib>Milhau, Julien</creatorcontrib><creatorcontrib>Onidi, Loredana</creatorcontrib><creatorcontrib>Paparin, Jean-Laurent</creatorcontrib><creatorcontrib>Rahali, Rachid</creatorcontrib><creatorcontrib>Sais, Efisio</creatorcontrib><creatorcontrib>Seifer, Maria</creatorcontrib><creatorcontrib>Surleraux, Dominique</creatorcontrib><creatorcontrib>Standring, David</creatorcontrib><creatorcontrib>Dousson, Cyril</creatorcontrib><title>Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. 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The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27520942</pmid><doi>10.1016/j.bmcl.2016.01.042</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2016-09, Vol.26 (18), p.4536-4541 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Allosteric inhibitors Allosteric Site Amide bioisostere Antiviral Agents - chemistry Antiviral Agents - metabolism Antiviral Agents - pharmacology Crystallography, X-Ray Direct-acting antivirals Genotype Hepacivirus - drug effects Hepatitis C virus NS5B non-nucleoside inhibitors Polymerase inhibitors Structure-Activity Relationship Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism |
| title | Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase |
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