Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors
NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (10), p.3488-3491 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Shi, Junxing Zhou, Longhu Amblard, Franck Bobeck, Drew R. Zhang, Hongwang Liu, Peng Bondada, Lavanya McBrayer, Tamara R. Tharnish, Phillip M. Whitaker, Tony Coats, Steven J. Schinazi, Raymond F. |
| description | NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC50 value of 26pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent. |
| doi_str_mv | 10.1016/j.bmcl.2012.03.089 |
| format | Article |
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Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC50 value of 26pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.03.089</identifier><identifier>PMID: 22507961</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Antibiotics. Antiinfectious agents. 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Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC50 value of 26pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>biphenyl</subject><subject>Cell Line</subject><subject>chemistry</subject><subject>cytotoxicity</subject><subject>genotype</subject><subject>HCV</subject><subject>Hepacivirus - drug effects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>NS5A inhibitor</subject><subject>Pharmacology. Drug treatments</subject><subject>replicon</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1uEzEURi0EoqHwAixgNl3OcP0bW0JIVQQUqWoXoYidZXs8iaOJHdnToL49Dilt2bDywuf77tW5CL3F0GHA4sOms1s3dgQw6YB2INUzNMNMsJYy4M_RDJSAVir28wS9KmUDgBkw9hKdEMJhrgSeoeXyLk5rX0JpTOwbG9KYVsGZsfF7M96aKaTYpKGJ_lezS5OP0x-u-NG7Kex9c7H40Vwt-XkT4jrYMKVcXqMXgxmLf3P_nqKbL5-_Ly7ay-uv3xbnl63joKbWMGJ6KyyTwmLjsDIWS4oleMEH53sxSKu4tRzjnlA2eIsxZk5SZSTp54Seok_H3t2t3fre1eWyGfUuh63JdzqZoP_9iWGtV2mv53NKgLBaQI4FLqdSsh8eshj0QbHe6INifVCsgeqquIbePZ36EPnrtAJn94ApVeSQTXShPHJcSsmVrNz7IzeYpM0qV-ZmWSfxeicKgh-aPh4JXy3ug8-6uOBjdRNy1a_7FP636W8YTqT0</recordid><startdate>20120515</startdate><enddate>20120515</enddate><creator>Shi, Junxing</creator><creator>Zhou, Longhu</creator><creator>Amblard, Franck</creator><creator>Bobeck, Drew R.</creator><creator>Zhang, Hongwang</creator><creator>Liu, Peng</creator><creator>Bondada, Lavanya</creator><creator>McBrayer, Tamara R.</creator><creator>Tharnish, Phillip M.</creator><creator>Whitaker, Tony</creator><creator>Coats, Steven J.</creator><creator>Schinazi, Raymond F.</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20120515</creationdate><title>Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors</title><author>Shi, Junxing ; Zhou, Longhu ; Amblard, Franck ; Bobeck, Drew R. ; Zhang, Hongwang ; Liu, Peng ; Bondada, Lavanya ; McBrayer, Tamara R. ; Tharnish, Phillip M. ; Whitaker, Tony ; Coats, Steven J. ; Schinazi, Raymond F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-a42adb6b486b1ac19ab183180e65fced6f8b95bb511d234feb1114c839a82d723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antibiotics. 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| ispartof | Bioorganic & medicinal chemistry letters, 2012-05, Vol.22 (10), p.3488-3491 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - pharmacology Biological and medical sciences biphenyl Cell Line chemistry cytotoxicity genotype HCV Hepacivirus - drug effects Humans Medical sciences Microbial Sensitivity Tests NS5A inhibitor Pharmacology. Drug treatments replicon Viral Nonstructural Proteins - antagonists & inhibitors |
| title | Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors |
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