Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents
As an extension of our earlier work based upon a single penicillin-derived thiazolidine moiety we have found that the decahydroisoquinoline grouping, also present in Ro 31-8959, is an effective replacement for one of the thiazolidine units in C2 symmetric penicillin-derived dimers. Reaction of racem...
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| Veröffentlicht in: | Journal of medicinal chemistry 1994-10, Vol.37 (22), p.3707-3716 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Kitchin, John Bethell, Richard C Cammack, Nicholas Dolan, Simon Evans, Derek N Holman, Stuart Holmes, Duncan S McMeekin, Peter Mo, Chi L |
| description | As an extension of our earlier work based upon a single penicillin-derived thiazolidine moiety we have found that the decahydroisoquinoline grouping, also present in Ro 31-8959, is an effective replacement for one of the thiazolidine units in C2 symmetric penicillin-derived dimers. Reaction of racemic epoxide 6 with [3S-[3 alpha, 4a alpha, 8a alpha]]-decahydro-N-(1,1-dimethylethyl)-3- isoquinolinecarboxamide gave diasteroisomers 34a and 34b. The stereochemistry of the hydroxyl grouping of 34a was determined to be (S). Reaction of the amines derived from 34a and 34b with thiazolidine 8a gave 50 and 51, respectively. Compound 50 was a potent inhibitor of HIV proteinase (IC50 = 23 nM) with antiviral activity against HIV-1 in vitro (EC50 C8166 cells = 50 nM). However, a poor pharmacokinetic profile in the dog for compound 50 and its analogues, in keeping with earlier studies on penicillin-derived dimers in three species, precluded their development as potential antivirals. |
| doi_str_mv | 10.1021/jm00048a007 |
| format | Article |
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Reaction of racemic epoxide 6 with [3S-[3 alpha, 4a alpha, 8a alpha]]-decahydro-N-(1,1-dimethylethyl)-3- isoquinolinecarboxamide gave diasteroisomers 34a and 34b. The stereochemistry of the hydroxyl grouping of 34a was determined to be (S). Reaction of the amines derived from 34a and 34b with thiazolidine 8a gave 50 and 51, respectively. Compound 50 was a potent inhibitor of HIV proteinase (IC50 = 23 nM) with antiviral activity against HIV-1 in vitro (EC50 C8166 cells = 50 nM). However, a poor pharmacokinetic profile in the dog for compound 50 and its analogues, in keeping with earlier studies on penicillin-derived dimers in three species, precluded their development as potential antivirals.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00048a007</identifier><identifier>PMID: 7966131</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>AIDS/HIV ; Amino Acid Sequence ; Animals ; Cell Line ; Computer Graphics ; Crystallography, X-Ray ; Dogs ; Giant Cells - drug effects ; HIV Protease Inhibitors - chemical synthesis ; HIV Protease Inhibitors - pharmacology ; HIV-1 - enzymology ; Molecular Sequence Data ; Penicillins - chemical synthesis ; Penicillins - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1994-10, Vol.37 (22), p.3707-3716</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a269t-eaf39130d870c62e74ff47f0f9cd4070276e2bf62f3310d6986679c3462ea59b3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00048a007$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00048a007$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7966131$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kitchin, John</creatorcontrib><creatorcontrib>Bethell, Richard C</creatorcontrib><creatorcontrib>Cammack, Nicholas</creatorcontrib><creatorcontrib>Dolan, Simon</creatorcontrib><creatorcontrib>Evans, Derek N</creatorcontrib><creatorcontrib>Holman, Stuart</creatorcontrib><creatorcontrib>Holmes, Duncan S</creatorcontrib><creatorcontrib>McMeekin, Peter</creatorcontrib><creatorcontrib>Mo, Chi L</creatorcontrib><title>Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>As an extension of our earlier work based upon a single penicillin-derived thiazolidine moiety we have found that the decahydroisoquinoline grouping, also present in Ro 31-8959, is an effective replacement for one of the thiazolidine units in C2 symmetric penicillin-derived dimers. Reaction of racemic epoxide 6 with [3S-[3 alpha, 4a alpha, 8a alpha]]-decahydro-N-(1,1-dimethylethyl)-3- isoquinolinecarboxamide gave diasteroisomers 34a and 34b. The stereochemistry of the hydroxyl grouping of 34a was determined to be (S). Reaction of the amines derived from 34a and 34b with thiazolidine 8a gave 50 and 51, respectively. Compound 50 was a potent inhibitor of HIV proteinase (IC50 = 23 nM) with antiviral activity against HIV-1 in vitro (EC50 C8166 cells = 50 nM). However, a poor pharmacokinetic profile in the dog for compound 50 and its analogues, in keeping with earlier studies on penicillin-derived dimers in three species, precluded their development as potential antivirals.</description><subject>AIDS/HIV</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Computer Graphics</subject><subject>Crystallography, X-Ray</subject><subject>Dogs</subject><subject>Giant Cells - drug effects</subject><subject>HIV Protease Inhibitors - chemical synthesis</subject><subject>HIV Protease Inhibitors - pharmacology</subject><subject>HIV-1 - enzymology</subject><subject>Molecular Sequence Data</subject><subject>Penicillins - chemical synthesis</subject><subject>Penicillins - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU9v1DAQxS0EKkvhxBnJJ_aAAv6TtRNu1UK7iyqImtIDF8txxqyXrLPYTkU-Ur8laXdVceA0o3k_zYzeQ-g1Je8pYfTDdkcIyQtNiHyCZnTBSJYXJH-KZoQwljHB-HP0IsbthHHK-Ak6kaUQlNMZuqtHnzYQXcTat7hOYTBpCJCdmeRuXRrxFXQ6ud7HjdtH3FuscQ3BwUNfgXfGdZ3z2adpeAstXq1vcBX6BM7rCHjtN65xqQ_xI15BgtCb0XTO4Cvnf-J6jAl2ES97n7Tz96OKzh9eqdgc10MTk0sD-BRfomdWdxFeHesp-n7--Xq5yi6_XayXZ5eZZqJMGWjLS8pJW0hiBAOZW5tLS2xp2pxIwqQA1ljBLOeUtKIshJCl4fnE6kXZ8FP09rB3H_rfA8Skdi4a6DrtoR-ikqKYHM3LCXx3AE3oYwxg1T64nQ6jokTdB6P-CWai3xzXDs0O2kf2mMSkZwfdTY78eZR1-KWE5HKhrqtafeGkPr9hP9TXiZ8feG2i2vZD8JMp_738FyHFpgc</recordid><startdate>19941001</startdate><enddate>19941001</enddate><creator>Kitchin, John</creator><creator>Bethell, Richard C</creator><creator>Cammack, Nicholas</creator><creator>Dolan, Simon</creator><creator>Evans, Derek N</creator><creator>Holman, Stuart</creator><creator>Holmes, Duncan S</creator><creator>McMeekin, Peter</creator><creator>Mo, Chi L</creator><general>American Chemical Society</general><scope>BSCLL</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></search><sort><creationdate>19941001</creationdate><title>Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents</title><author>Kitchin, John ; Bethell, Richard C ; Cammack, Nicholas ; Dolan, Simon ; Evans, Derek N ; Holman, Stuart ; Holmes, Duncan S ; McMeekin, Peter ; Mo, Chi L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a269t-eaf39130d870c62e74ff47f0f9cd4070276e2bf62f3310d6986679c3462ea59b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>AIDS/HIV</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Computer Graphics</topic><topic>Crystallography, X-Ray</topic><topic>Dogs</topic><topic>Giant Cells - drug effects</topic><topic>HIV Protease Inhibitors - chemical synthesis</topic><topic>HIV Protease Inhibitors - pharmacology</topic><topic>HIV-1 - enzymology</topic><topic>Molecular Sequence Data</topic><topic>Penicillins - chemical synthesis</topic><topic>Penicillins - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kitchin, John</creatorcontrib><creatorcontrib>Bethell, Richard C</creatorcontrib><creatorcontrib>Cammack, Nicholas</creatorcontrib><creatorcontrib>Dolan, Simon</creatorcontrib><creatorcontrib>Evans, Derek N</creatorcontrib><creatorcontrib>Holman, Stuart</creatorcontrib><creatorcontrib>Holmes, Duncan S</creatorcontrib><creatorcontrib>McMeekin, Peter</creatorcontrib><creatorcontrib>Mo, Chi L</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kitchin, John</au><au>Bethell, Richard C</au><au>Cammack, Nicholas</au><au>Dolan, Simon</au><au>Evans, Derek N</au><au>Holman, Stuart</au><au>Holmes, Duncan S</au><au>McMeekin, Peter</au><au>Mo, Chi L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-10-01</date><risdate>1994</risdate><volume>37</volume><issue>22</issue><spage>3707</spage><epage>3716</epage><pages>3707-3716</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>As an extension of our earlier work based upon a single penicillin-derived thiazolidine moiety we have found that the decahydroisoquinoline grouping, also present in Ro 31-8959, is an effective replacement for one of the thiazolidine units in C2 symmetric penicillin-derived dimers. Reaction of racemic epoxide 6 with [3S-[3 alpha, 4a alpha, 8a alpha]]-decahydro-N-(1,1-dimethylethyl)-3- isoquinolinecarboxamide gave diasteroisomers 34a and 34b. The stereochemistry of the hydroxyl grouping of 34a was determined to be (S). Reaction of the amines derived from 34a and 34b with thiazolidine 8a gave 50 and 51, respectively. Compound 50 was a potent inhibitor of HIV proteinase (IC50 = 23 nM) with antiviral activity against HIV-1 in vitro (EC50 C8166 cells = 50 nM). However, a poor pharmacokinetic profile in the dog for compound 50 and its analogues, in keeping with earlier studies on penicillin-derived dimers in three species, precluded their development as potential antivirals.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>7966131</pmid><doi>10.1021/jm00048a007</doi><tpages>10</tpages></addata></record> |
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| source | MEDLINE; ACS Publications |
| subjects | AIDS/HIV Amino Acid Sequence Animals Cell Line Computer Graphics Crystallography, X-Ray Dogs Giant Cells - drug effects HIV Protease Inhibitors - chemical synthesis HIV Protease Inhibitors - pharmacology HIV-1 - enzymology Molecular Sequence Data Penicillins - chemical synthesis Penicillins - pharmacology Structure-Activity Relationship |
| title | Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents |
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