Development of a Novel Series of Trialkoxyaryl Derivatives as Specific and Competitive Antagonists of Platelet Activating Factor
The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led t...
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| Veröffentlicht in: | Journal of medicinal chemistry 1995-06, Vol.38 (12), p.2130-2137 |
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| container_end_page | 2137 |
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| container_issue | 12 |
| container_start_page | 2130 |
| container_title | Journal of medicinal chemistry |
| container_volume | 38 |
| creator | Beams, Richard M Blackwell, Geoffrey J Brockwell, Michael A Cheesman, Neil J Demaine, Derek A Garland, Lawrence G Hodson, Harold F Hyde, Richard M Islip, Peter J |
| description | The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets. |
| doi_str_mv | 10.1021/jm00012a012 |
| format | Article |
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Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00012a012</identifier><identifier>PMID: 7783144</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Binding Sites ; Blood Platelets - drug effects ; Blood Platelets - metabolism ; Cells, Cultured ; Male ; Platelet Activating Factor - antagonists & inhibitors ; Platelet Aggregation Inhibitors - pharmacology ; Quaternary Ammonium Compounds - chemical synthesis ; Quaternary Ammonium Compounds - metabolism ; Quaternary Ammonium Compounds - pharmacology ; Rabbits ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1995-06, Vol.38 (12), p.2130-2137</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a354t-254a0d89b86c2b1a6569a2c89c7f19f1e4f0344c32efd9b00dd4b19371078f123</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/jm00012a012$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00012a012$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7783144$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Beams, Richard M</creatorcontrib><creatorcontrib>Blackwell, Geoffrey J</creatorcontrib><creatorcontrib>Brockwell, Michael A</creatorcontrib><creatorcontrib>Cheesman, Neil J</creatorcontrib><creatorcontrib>Demaine, Derek A</creatorcontrib><creatorcontrib>Garland, Lawrence G</creatorcontrib><creatorcontrib>Hodson, Harold F</creatorcontrib><creatorcontrib>Hyde, Richard M</creatorcontrib><creatorcontrib>Islip, Peter J</creatorcontrib><title>Development of a Novel Series of Trialkoxyaryl Derivatives as Specific and Competitive Antagonists of Platelet Activating Factor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Blood Platelets - drug effects</subject><subject>Blood Platelets - metabolism</subject><subject>Cells, Cultured</subject><subject>Male</subject><subject>Platelet Activating Factor - antagonists & inhibitors</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Quaternary Ammonium Compounds - chemical synthesis</subject><subject>Quaternary Ammonium Compounds - metabolism</subject><subject>Quaternary Ammonium Compounds - pharmacology</subject><subject>Rabbits</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1vEzEQxS1EVULhxBnJJzigpf7a9e4xJLRFqkpFwtnyeseV0931YjtRe-NPx2miikMPI0vv_eZZ8xD6QMlXShg93wyEEMp0nldoRktGClET8RrNCGGsYBXjb9DbGDcZ45TxU3QqZc2pEDP0dwk76P00wJiwt1jjG58FvILgIO6VdXC6v_cPjzo89niZ9Z1ObpdNHfFqAuOsM1iPHV74YYLk9iaej0nf-dHF9BRy2-sEPSQ8N-lpf7zDF9okH96hE6v7CO-P7xn6ffF9vbgqrn9e_ljMrwvNS5EKVgpNurpp68qwluqqrBrNTN0YaWljKQhLuBCGM7Bd0xLSdaKlDZeUyNrmo8_Qp0PuFPyfLcSkBhcN9L0ewW-jkpLzpqp5Br8cQBN8jAGsmoIb8vGKErXvW_3Xd6Y_HmO37QDdM3ssOPvFwc9NwMOzrcO9qiSXpVrfrpSovzXL9a9SVZn_fOC1iWrjt2HMpbz48z9_5Jdw</recordid><startdate>19950601</startdate><enddate>19950601</enddate><creator>Beams, Richard M</creator><creator>Blackwell, Geoffrey J</creator><creator>Brockwell, Michael A</creator><creator>Cheesman, Neil J</creator><creator>Demaine, Derek A</creator><creator>Garland, Lawrence G</creator><creator>Hodson, Harold F</creator><creator>Hyde, Richard M</creator><creator>Islip, Peter J</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>19950601</creationdate><title>Development of a Novel Series of Trialkoxyaryl Derivatives as Specific and Competitive Antagonists of Platelet Activating Factor</title><author>Beams, Richard M ; Blackwell, Geoffrey J ; Brockwell, Michael A ; Cheesman, Neil J ; Demaine, Derek A ; Garland, Lawrence G ; Hodson, Harold F ; Hyde, Richard M ; Islip, Peter J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a354t-254a0d89b86c2b1a6569a2c89c7f19f1e4f0344c32efd9b00dd4b19371078f123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Blood Platelets - drug effects</topic><topic>Blood Platelets - metabolism</topic><topic>Cells, Cultured</topic><topic>Male</topic><topic>Platelet Activating Factor - antagonists & inhibitors</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Quaternary Ammonium Compounds - chemical synthesis</topic><topic>Quaternary Ammonium Compounds - metabolism</topic><topic>Quaternary Ammonium Compounds - pharmacology</topic><topic>Rabbits</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Beams, Richard M</creatorcontrib><creatorcontrib>Blackwell, Geoffrey J</creatorcontrib><creatorcontrib>Brockwell, Michael A</creatorcontrib><creatorcontrib>Cheesman, Neil J</creatorcontrib><creatorcontrib>Demaine, Derek A</creatorcontrib><creatorcontrib>Garland, Lawrence G</creatorcontrib><creatorcontrib>Hodson, Harold F</creatorcontrib><creatorcontrib>Hyde, Richard M</creatorcontrib><creatorcontrib>Islip, Peter J</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>Beams, Richard M</au><au>Blackwell, Geoffrey J</au><au>Brockwell, Michael A</au><au>Cheesman, Neil J</au><au>Demaine, Derek A</au><au>Garland, Lawrence G</au><au>Hodson, Harold F</au><au>Hyde, Richard M</au><au>Islip, Peter J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of a Novel Series of Trialkoxyaryl Derivatives as Specific and Competitive Antagonists of Platelet Activating Factor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1995-06-01</date><risdate>1995</risdate><volume>38</volume><issue>12</issue><spage>2130</spage><epage>2137</epage><pages>2130-2137</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>7783144</pmid><doi>10.1021/jm00012a012</doi><tpages>8</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1995-06, Vol.38 (12), p.2130-2137 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Binding Sites Blood Platelets - drug effects Blood Platelets - metabolism Cells, Cultured Male Platelet Activating Factor - antagonists & inhibitors Platelet Aggregation Inhibitors - pharmacology Quaternary Ammonium Compounds - chemical synthesis Quaternary Ammonium Compounds - metabolism Quaternary Ammonium Compounds - pharmacology Rabbits Structure-Activity Relationship |
| title | Development of a Novel Series of Trialkoxyaryl Derivatives as Specific and Competitive Antagonists of Platelet Activating Factor |
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