Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors
This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency i...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-12, Vol.24 (24), p.5731-5737 |
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| container_issue | 24 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Zhong, Min Peng, Eric Huang, Ningwu Huang, Qi Huq, Anja Lau, Meiyen Colonno, Richard Li, Leping |
| description | This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration. |
| doi_str_mv | 10.1016/j.bmcl.2014.10.057 |
| format | Article |
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Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.10.057</identifier><identifier>PMID: 25453810</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacokinetics ; Antiviral Agents - pharmacology ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - virology ; Drug Discovery ; Drug Evaluation, Preclinical ; Hepacivirus - drug effects ; Hepatitis C - drug therapy ; Hepatitis C - virology ; Hepatitis C virus ; Humans ; Hydrocarbons, Acyclic - chemistry ; Imidazoles - chemistry ; Liver Neoplasms - drug therapy ; Liver Neoplasms - virology ; Male ; Models, Molecular ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Replicon - drug effects ; Structure-Activity Relationship ; Tumor Cells, Cultured ; Viral Nonstructural Proteins - antagonists & inhibitors ; Virus Replication - drug effects</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-12, Vol.24 (24), p.5731-5737</ispartof><rights>Copyright © 2014 Elsevier Ltd. 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Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.</description><subject>Animals</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Antiviral Agents - pharmacology</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - virology</subject><subject>Drug Discovery</subject><subject>Drug Evaluation, Preclinical</subject><subject>Hepacivirus - drug effects</subject><subject>Hepatitis C - drug therapy</subject><subject>Hepatitis C - virology</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Hydrocarbons, Acyclic - chemistry</subject><subject>Imidazoles - chemistry</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - virology</subject><subject>Male</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Replicon - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Virus Replication - drug effects</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMlOwzAURS0EoqXwAyyQl2wS7HhIvazKUKQKFgxiFzmO3bpy4hAnSOnXk6iF1ZOuzr3SOwBcYxRjhPndLs5L5eIEYToEMWLpCZhiymlEKGKnYIoER9Fc0K8JuAhhhwYQUXoOJgmjjMwxmoLNvQ3K_-imh95A01Wqtb6Szu51AXMbbGkLufdOB5hr2dhqA1WvnFVwYOqtbK2K6q2uegdL31oToAxwtfyEL29sAW21tbltfRMuwZmRLuir452Bj8eH9-UqWr8-PS8X60gRwtsICyZMQWUqJCFpijBDrFAUG8aokEUyZzkTks1RwXEqVMqVSWiik5QqobXhZAZuD7t14787HdqsHB7UzslK-y5kmHNEBiWJGNDkgKrGh9Bok9WNLWXTZxhlo-Bsl42Cs1HwmA2Ch9LNcb_LS138V_6Mkl9oy3hj</recordid><startdate>20141215</startdate><enddate>20141215</enddate><creator>Zhong, Min</creator><creator>Peng, Eric</creator><creator>Huang, Ningwu</creator><creator>Huang, Qi</creator><creator>Huq, Anja</creator><creator>Lau, Meiyen</creator><creator>Colonno, Richard</creator><creator>Li, Leping</creator><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>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20141215</creationdate><title>Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors</title><author>Zhong, Min ; 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| ispartof | Bioorganic & medicinal chemistry letters, 2014-12, Vol.24 (24), p.5731-5737 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Animals Antiviral Agents - chemistry Antiviral Agents - pharmacokinetics Antiviral Agents - pharmacology Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - virology Drug Discovery Drug Evaluation, Preclinical Hepacivirus - drug effects Hepatitis C - drug therapy Hepatitis C - virology Hepatitis C virus Humans Hydrocarbons, Acyclic - chemistry Imidazoles - chemistry Liver Neoplasms - drug therapy Liver Neoplasms - virology Male Models, Molecular Molecular Structure Rats Rats, Sprague-Dawley Replicon - drug effects Structure-Activity Relationship Tumor Cells, Cultured Viral Nonstructural Proteins - antagonists & inhibitors Virus Replication - drug effects |
| title | Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors |
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