Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease
A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as we...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (12), p.3568-3572 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Clarke, Michael O. Chen, Xiaowu Cho, Aesop Delaney, William E. Doerffler, Edward Fardis, Maria Ji, Mingzhe Mertzman, Michael Pakdaman, Rowchanak Pyun, Hyun-Jun Rowe, Tanisha Yang, Cheng Y. Sheng, X. Christopher Kim, Choung U. |
| description | A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described. |
| doi_str_mv | 10.1016/j.bmcl.2011.04.125 |
| format | Article |
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Christopher ; Kim, Choung U.</creator><creatorcontrib>Clarke, Michael O. ; Chen, Xiaowu ; Cho, Aesop ; Delaney, William E. ; Doerffler, Edward ; Fardis, Maria ; Ji, Mingzhe ; Mertzman, Michael ; Pakdaman, Rowchanak ; Pyun, Hyun-Jun ; Rowe, Tanisha ; Yang, Cheng Y. ; Sheng, X. Christopher ; Kim, Choung U.</creatorcontrib><description>A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.04.125</identifier><identifier>PMID: 21601450</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Biological and medical sciences ; Carboxylate isostere ; Cyclization ; HCV ; Hepacivirus - drug effects ; Hepacivirus - enzymology ; Hepatitis C virus ; Humans ; Inhibitory Concentration 50 ; Medical sciences ; Molecular Structure ; NS3 protease ; pharmacokinetics ; Pharmacology. Drug treatments ; Phosphinic acid ; Phosphinic Acids - chemical synthesis ; Phosphinic Acids - chemistry ; Phosphinic Acids - pharmacology ; proteinases ; replicon ; Viral Nonstructural Proteins - antagonists & inhibitors</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-06, Vol.21 (12), p.3568-3572</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-ee5e3cd7cd4472e5ed3cc1d6ce96850097c37bfc37983f909f1fba7e5ad161543</citedby><cites>FETCH-LOGICAL-c441t-ee5e3cd7cd4472e5ed3cc1d6ce96850097c37bfc37983f909f1fba7e5ad161543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2011.04.125$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24301825$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21601450$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Clarke, Michael O.</creatorcontrib><creatorcontrib>Chen, Xiaowu</creatorcontrib><creatorcontrib>Cho, Aesop</creatorcontrib><creatorcontrib>Delaney, William E.</creatorcontrib><creatorcontrib>Doerffler, Edward</creatorcontrib><creatorcontrib>Fardis, Maria</creatorcontrib><creatorcontrib>Ji, Mingzhe</creatorcontrib><creatorcontrib>Mertzman, Michael</creatorcontrib><creatorcontrib>Pakdaman, Rowchanak</creatorcontrib><creatorcontrib>Pyun, Hyun-Jun</creatorcontrib><creatorcontrib>Rowe, Tanisha</creatorcontrib><creatorcontrib>Yang, Cheng Y.</creatorcontrib><creatorcontrib>Sheng, X. Christopher</creatorcontrib><creatorcontrib>Kim, Choung U.</creatorcontrib><title>Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.</description><subject>Administration, Oral</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Biological and medical sciences</subject><subject>Carboxylate isostere</subject><subject>Cyclization</subject><subject>HCV</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - enzymology</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>NS3 protease</subject><subject>pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphinic acid</subject><subject>Phosphinic Acids - chemical synthesis</subject><subject>Phosphinic Acids - chemistry</subject><subject>Phosphinic Acids - pharmacology</subject><subject>proteinases</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>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU9v1DAQxS0EotvCF-AAviAuTRjHzh9LvaAVBaSqHEolbpZjTxqvvHGwsyv12-NlF7ghLh6P9Js3o_cIecWgZMCa95uy3xpfVsBYCaJkVf2ErJhoRMEF1E_JCmQDRSfF9zNyntIGgAkQ4jk5q1iT_zWsyMNt2KO_pHNYcFouqZ4sDVF7_0h7F_ReO697j3QeQ5pHNzlDtXGWuml0vVtCTDQMdBmRjjjrxS0u0TXdu7hL9PaO0zlmYZ3wBXk2aJ_w5alekPvrj9_Wn4ubr5--rD_cFEYIthSINXJjW2OFaKvcWG4Ms41B2XQ1gGwNb_shP7LjgwQ5sKHXLdbasobVgl-Qd0fdvPjHDtOiti4Z9F5PGHZJda1gXVN37D9IqGS2CzJZHUkTQ0oRBzVHt9XxUTFQhyTURh2SUIckFAiVk8hDr0_yu36L9s_Ib-sz8PYE6GS0H6KejEt_OcGBdb-E3hy5QQelH2Jm7u_ypuwG46KTPBNXRwKzsXuHUSXjcDJoXUSzKBvcvy79CVFVsEI</recordid><startdate>20110615</startdate><enddate>20110615</enddate><creator>Clarke, Michael O.</creator><creator>Chen, Xiaowu</creator><creator>Cho, Aesop</creator><creator>Delaney, William E.</creator><creator>Doerffler, Edward</creator><creator>Fardis, Maria</creator><creator>Ji, Mingzhe</creator><creator>Mertzman, Michael</creator><creator>Pakdaman, Rowchanak</creator><creator>Pyun, Hyun-Jun</creator><creator>Rowe, Tanisha</creator><creator>Yang, Cheng Y.</creator><creator>Sheng, X. Christopher</creator><creator>Kim, Choung U.</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>7X8</scope><scope>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20110615</creationdate><title>Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease</title><author>Clarke, Michael O. ; Chen, Xiaowu ; Cho, Aesop ; Delaney, William E. ; Doerffler, Edward ; Fardis, Maria ; Ji, Mingzhe ; Mertzman, Michael ; Pakdaman, Rowchanak ; Pyun, Hyun-Jun ; Rowe, Tanisha ; Yang, Cheng Y. ; Sheng, X. Christopher ; Kim, Choung U.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-ee5e3cd7cd4472e5ed3cc1d6ce96850097c37bfc37983f909f1fba7e5ad161543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Biological and medical sciences</topic><topic>Carboxylate isostere</topic><topic>Cyclization</topic><topic>HCV</topic><topic>Hepacivirus - drug effects</topic><topic>Hepacivirus - enzymology</topic><topic>Hepatitis C virus</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>NS3 protease</topic><topic>pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphinic acid</topic><topic>Phosphinic Acids - chemical synthesis</topic><topic>Phosphinic Acids - chemistry</topic><topic>Phosphinic Acids - pharmacology</topic><topic>proteinases</topic><topic>replicon</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clarke, Michael O.</creatorcontrib><creatorcontrib>Chen, Xiaowu</creatorcontrib><creatorcontrib>Cho, Aesop</creatorcontrib><creatorcontrib>Delaney, William E.</creatorcontrib><creatorcontrib>Doerffler, Edward</creatorcontrib><creatorcontrib>Fardis, Maria</creatorcontrib><creatorcontrib>Ji, Mingzhe</creatorcontrib><creatorcontrib>Mertzman, Michael</creatorcontrib><creatorcontrib>Pakdaman, Rowchanak</creatorcontrib><creatorcontrib>Pyun, Hyun-Jun</creatorcontrib><creatorcontrib>Rowe, Tanisha</creatorcontrib><creatorcontrib>Yang, Cheng Y.</creatorcontrib><creatorcontrib>Sheng, X. 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Christopher</au><au>Kim, Choung U.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-06-15</date><risdate>2011</risdate><volume>21</volume><issue>12</issue><spage>3568</spage><epage>3572</epage><pages>3568-3572</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21601450</pmid><doi>10.1016/j.bmcl.2011.04.125</doi><tpages>5</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2011-06, Vol.21 (12), p.3568-3572 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Carboxylate isostere Cyclization HCV Hepacivirus - drug effects Hepacivirus - enzymology Hepatitis C virus Humans Inhibitory Concentration 50 Medical sciences Molecular Structure NS3 protease pharmacokinetics Pharmacology. Drug treatments Phosphinic acid Phosphinic Acids - chemical synthesis Phosphinic Acids - chemistry Phosphinic Acids - pharmacology proteinases replicon Viral Nonstructural Proteins - antagonists & inhibitors |
| title | Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease |
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