Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors
We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical an...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-11, Vol.49 (24), p.6950-6953 |
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| container_issue | 24 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 49 |
| creator | Ikegashira, Kazutaka Oka, Takahiro Hirashima, Shintaro Noji, Satoru Yamanaka, Hiroshi Hara, Yoshinori Adachi, Tsuyoshi Tsuruha, Jun-Ichiro Doi, Satoki Hase, Yasunori Noguchi, Toru Ando, Izuru Ogura, Naoki Ikeda, Satoru Hashimoto, Hiromasa |
| description | We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin. |
| doi_str_mv | 10.1021/jm0610245 |
| format | Article |
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SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0610245</identifier><identifier>PMID: 17125247</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Benzodiazepines - chemical synthesis ; Benzodiazepines - chemistry ; Benzodiazepines - pharmacology ; Biological and medical sciences ; Crystallography, X-Ray ; Hepacivirus - enzymology ; Hepacivirus - genetics ; Hepatitis C virus ; Heterocyclic Compounds, 4 or More Rings - chemical synthesis ; Heterocyclic Compounds, 4 or More Rings - chemistry ; Heterocyclic Compounds, 4 or More Rings - pharmacology ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Medical sciences ; Models, Molecular ; Molecular Conformation ; Pharmacology. 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Med. Chem</addtitle><description>We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Benzodiazepines - chemical synthesis</subject><subject>Benzodiazepines - chemistry</subject><subject>Benzodiazepines - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Hepacivirus - enzymology</subject><subject>Hepacivirus - genetics</subject><subject>Hepatitis C virus</subject><subject>Heterocyclic Compounds, 4 or More Rings - chemical synthesis</subject><subject>Heterocyclic Compounds, 4 or More Rings - chemistry</subject><subject>Heterocyclic Compounds, 4 or More Rings - pharmacology</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Pharmacology. Drug treatments</subject><subject>Replicon</subject><subject>RNA, Viral - genetics</subject><subject>Serum Albumin</subject><subject>Structure-Activity Relationship</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c9v0zAUB3ALMbEyOPAPIF9A4hDmn4lzXDvKJlVj2kqvluM4wiWJO78EEf56PLVaL5N28tPzx09--iL0gZKvlDB6vu1IngohX6EZlYxkQhHxGs0IYSxjOeOn6C3AlhDCKeNv0CktKJNMFDP079KDDX9cnHBo8CL0TYidGXzoTdtOjw0YovG9q_HapcpOtvU29btdGPsasAF8GwbXD_jK7dLDwQNe4I2PI-CbeznHdzcXSbRT56IBh6_7X77yQ4jwDp00pgX3_nCeoZ_Lb-vFVbb68f16cbHKjCjUkLlKSWaaiuSV5EaykspG0qagjkiSl7KoVVWlpY3hgltL6zoXoqQsF5aVDRP8DH3ez93F8DA6GHSXdnZta3oXRtC5oiovSvkipGXBpZA8wS97aGMAiK7Ru-g7EydNiX5MRD8lkuzHw9Cx6lx9lIcIEvh0AAasaZtoeuvh6BRnUqkyuWzvPAzu79O9ib91XvBC6vXtvd4sV5fz5d1Gz49zjQW9DWNMicIzH_wPQeCt2A</recordid><startdate>20061130</startdate><enddate>20061130</enddate><creator>Ikegashira, Kazutaka</creator><creator>Oka, Takahiro</creator><creator>Hirashima, Shintaro</creator><creator>Noji, Satoru</creator><creator>Yamanaka, Hiroshi</creator><creator>Hara, Yoshinori</creator><creator>Adachi, Tsuyoshi</creator><creator>Tsuruha, Jun-Ichiro</creator><creator>Doi, Satoki</creator><creator>Hase, Yasunori</creator><creator>Noguchi, Toru</creator><creator>Ando, Izuru</creator><creator>Ogura, Naoki</creator><creator>Ikeda, Satoru</creator><creator>Hashimoto, Hiromasa</creator><general>American Chemical Society</general><scope>BSCLL</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>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20061130</creationdate><title>Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors</title><author>Ikegashira, Kazutaka ; Oka, Takahiro ; Hirashima, Shintaro ; Noji, Satoru ; Yamanaka, Hiroshi ; Hara, Yoshinori ; Adachi, Tsuyoshi ; Tsuruha, Jun-Ichiro ; Doi, Satoki ; Hase, Yasunori ; Noguchi, Toru ; Ando, Izuru ; Ogura, Naoki ; Ikeda, Satoru ; Hashimoto, Hiromasa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a478t-eb852afb06b53a52915f51f71e0506957d8bb520aa343cc1dd64491264c29f243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Antibiotics. 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Med. Chem</addtitle><date>2006-11-30</date><risdate>2006</risdate><volume>49</volume><issue>24</issue><spage>6950</spage><epage>6953</epage><pages>6950-6953</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17125247</pmid><doi>10.1021/jm0610245</doi><tpages>4</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2006-11, Vol.49 (24), p.6950-6953 |
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| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Benzodiazepines - chemical synthesis Benzodiazepines - chemistry Benzodiazepines - pharmacology Biological and medical sciences Crystallography, X-Ray Hepacivirus - enzymology Hepacivirus - genetics Hepatitis C virus Heterocyclic Compounds, 4 or More Rings - chemical synthesis Heterocyclic Compounds, 4 or More Rings - chemistry Heterocyclic Compounds, 4 or More Rings - pharmacology Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Medical sciences Models, Molecular Molecular Conformation Pharmacology. Drug treatments Replicon RNA, Viral - genetics Serum Albumin Structure-Activity Relationship Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - chemistry |
| title | Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors |
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