In Vitro Platelet-Activating Factor Receptor Binding Inhibitory Activity of Pinusolide Derivatives: A Structure−Activity Study
Pinusolide, a labdane-type diterpene lactone isolated from Biota orientalis, was found to be a potent platelet-activating factor (PAF) receptor binding antagonist. To investigate the structure−activity relationship and find derivatives with improved pharmacological profiles, 17 pinusolide derivative...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-07, Vol.41 (14), p.2626-2630 |
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| container_issue | 14 |
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| container_title | Journal of medicinal chemistry |
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| creator | Han, Byung Hoon Yang, Hyun Ok Kang, Young-Hwa Suh, Dae-Yeon Go, Hyun Jung Song, Wan-Jin Kim, Yong Chul Park, Man Ki |
| description | Pinusolide, a labdane-type diterpene lactone isolated from Biota orientalis, was found to be a potent platelet-activating factor (PAF) receptor binding antagonist. To investigate the structure−activity relationship and find derivatives with improved pharmacological profiles, 17 pinusolide derivatives were prepared and tested for their ability to inhibit the PAF receptor binding. The results demonstrated that the carboxymethyl ester group at C-19, the integrity of the α,β-unsaturated butenolide ring, and the exocyclic olefinic function of pinusolide are all necessary for its maximum PAF receptor binding inhibitory activity. Among the derivatives, the 17-nor-8-oxo derivative 8 was found to be as potent as pinusolide. The results also suggested that several derivatives warrant further pharmaceutical and pharmacological studies due to their improved water solubility (8 and 11) and apparent lack of susceptibility to Michael-type nucleophilic addition (13 and 18). |
| doi_str_mv | 10.1021/jm970569j |
| format | Article |
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To investigate the structure−activity relationship and find derivatives with improved pharmacological profiles, 17 pinusolide derivatives were prepared and tested for their ability to inhibit the PAF receptor binding. The results demonstrated that the carboxymethyl ester group at C-19, the integrity of the α,β-unsaturated butenolide ring, and the exocyclic olefinic function of pinusolide are all necessary for its maximum PAF receptor binding inhibitory activity. Among the derivatives, the 17-nor-8-oxo derivative 8 was found to be as potent as pinusolide. The results also suggested that several derivatives warrant further pharmaceutical and pharmacological studies due to their improved water solubility (8 and 11) and apparent lack of susceptibility to Michael-type nucleophilic addition (13 and 18).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970569j</identifier><identifier>PMID: 9651167</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Blood Platelets - drug effects ; Blood Platelets - metabolism ; Blood. Blood coagulation. Reticuloendothelial system ; Diterpenes - chemical synthesis ; Diterpenes - chemistry ; Diterpenes - pharmacology ; In Vitro Techniques ; Medical sciences ; Pharmacology. Drug treatments ; Platelet Activating Factor - metabolism ; Platelet Aggregation Inhibitors - chemical synthesis ; Platelet Aggregation Inhibitors - chemistry ; Platelet Aggregation Inhibitors - pharmacology ; Platelet Membrane Glycoproteins - antagonists & inhibitors ; Rabbits ; Receptors, Cell Surface ; Receptors, G-Protein-Coupled ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1998-07, Vol.41 (14), p.2626-2630</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a443t-1ff06b8a8c9129bb5a52a03998680d6a8885b11400de4ae7cb0bd2ab642532293</citedby><cites>FETCH-LOGICAL-a443t-1ff06b8a8c9129bb5a52a03998680d6a8885b11400de4ae7cb0bd2ab642532293</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm970569j$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm970569j$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2324432$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9651167$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Byung Hoon</creatorcontrib><creatorcontrib>Yang, Hyun Ok</creatorcontrib><creatorcontrib>Kang, Young-Hwa</creatorcontrib><creatorcontrib>Suh, Dae-Yeon</creatorcontrib><creatorcontrib>Go, Hyun Jung</creatorcontrib><creatorcontrib>Song, Wan-Jin</creatorcontrib><creatorcontrib>Kim, Yong Chul</creatorcontrib><creatorcontrib>Park, Man Ki</creatorcontrib><title>In Vitro Platelet-Activating Factor Receptor Binding Inhibitory Activity of Pinusolide Derivatives: A Structure−Activity Study</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Pinusolide, a labdane-type diterpene lactone isolated from Biota orientalis, was found to be a potent platelet-activating factor (PAF) receptor binding antagonist. To investigate the structure−activity relationship and find derivatives with improved pharmacological profiles, 17 pinusolide derivatives were prepared and tested for their ability to inhibit the PAF receptor binding. The results demonstrated that the carboxymethyl ester group at C-19, the integrity of the α,β-unsaturated butenolide ring, and the exocyclic olefinic function of pinusolide are all necessary for its maximum PAF receptor binding inhibitory activity. Among the derivatives, the 17-nor-8-oxo derivative 8 was found to be as potent as pinusolide. The results also suggested that several derivatives warrant further pharmaceutical and pharmacological studies due to their improved water solubility (8 and 11) and apparent lack of susceptibility to Michael-type nucleophilic addition (13 and 18).</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Platelets - drug effects</subject><subject>Blood Platelets - metabolism</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Diterpenes - chemical synthesis</subject><subject>Diterpenes - chemistry</subject><subject>Diterpenes - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Platelet Activating Factor - metabolism</subject><subject>Platelet Aggregation Inhibitors - chemical synthesis</subject><subject>Platelet Aggregation Inhibitors - chemistry</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Platelet Membrane Glycoproteins - antagonists & inhibitors</subject><subject>Rabbits</subject><subject>Receptors, Cell Surface</subject><subject>Receptors, G-Protein-Coupled</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1uEzEURi0EKqGw4AGQvAAkFlPsO38edqGlNFURUVNAYmNdezzgdDITbE9Fdiy77iPyJDhNNCtWtu53fHT9EfKcsyPOgL9drqqS5UW1fEAmPAeWZIJlD8mEMYAECkgfkyfeLxljKYf0gBxURc55UU7In1lHv9rgejpvMZjWhGSqg73BYLsf9BR16B29NNqst5f3tqu381n30yobJxt6T9uwoX1D57YbfN_a2tAT4-4lN8a_o1O6CG7QYXDm7-3d-GIRhnrzlDxqsPXm2f48JF9OP1wdnyUXnz_OjqcXCWZZGhLeNKxQAoWuOFRK5ZgDsrSqRCFYXaAQIlecZ4zVJkNTasVUDaiKDPIUoEoPyeudd-36X4PxQa6s16ZtsTP94GUZVTmAiOCbHahd770zjVw7u0K3kZzJbdtybDuyL_bSQa1MPZL7emP-cp-j19g2Djtt_YhBCvFzELFkh1kfzO8xRncto6TM5dV8IU8-nfPLs-9z-S3yr3Y8ai-X_eC62Nx_1vsHgyekrQ</recordid><startdate>19980702</startdate><enddate>19980702</enddate><creator>Han, Byung Hoon</creator><creator>Yang, Hyun Ok</creator><creator>Kang, Young-Hwa</creator><creator>Suh, Dae-Yeon</creator><creator>Go, Hyun Jung</creator><creator>Song, Wan-Jin</creator><creator>Kim, Yong Chul</creator><creator>Park, Man Ki</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>7X8</scope></search><sort><creationdate>19980702</creationdate><title>In Vitro Platelet-Activating Factor Receptor Binding Inhibitory Activity of Pinusolide Derivatives: A Structure−Activity Study</title><author>Han, Byung Hoon ; Yang, Hyun Ok ; Kang, Young-Hwa ; Suh, Dae-Yeon ; Go, Hyun Jung ; Song, Wan-Jin ; Kim, Yong Chul ; Park, Man Ki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a443t-1ff06b8a8c9129bb5a52a03998680d6a8885b11400de4ae7cb0bd2ab642532293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Platelets - drug effects</topic><topic>Blood Platelets - metabolism</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Diterpenes - chemical synthesis</topic><topic>Diterpenes - chemistry</topic><topic>Diterpenes - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Platelet Activating Factor - metabolism</topic><topic>Platelet Aggregation Inhibitors - chemical synthesis</topic><topic>Platelet Aggregation Inhibitors - chemistry</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Platelet Membrane Glycoproteins - antagonists & inhibitors</topic><topic>Rabbits</topic><topic>Receptors, Cell Surface</topic><topic>Receptors, G-Protein-Coupled</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Byung Hoon</creatorcontrib><creatorcontrib>Yang, Hyun Ok</creatorcontrib><creatorcontrib>Kang, Young-Hwa</creatorcontrib><creatorcontrib>Suh, Dae-Yeon</creatorcontrib><creatorcontrib>Go, Hyun Jung</creatorcontrib><creatorcontrib>Song, Wan-Jin</creatorcontrib><creatorcontrib>Kim, Yong Chul</creatorcontrib><creatorcontrib>Park, Man Ki</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</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>Han, Byung Hoon</au><au>Yang, Hyun Ok</au><au>Kang, Young-Hwa</au><au>Suh, Dae-Yeon</au><au>Go, Hyun Jung</au><au>Song, Wan-Jin</au><au>Kim, Yong Chul</au><au>Park, Man Ki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vitro Platelet-Activating Factor Receptor Binding Inhibitory Activity of Pinusolide Derivatives: A Structure−Activity Study</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-07-02</date><risdate>1998</risdate><volume>41</volume><issue>14</issue><spage>2626</spage><epage>2630</epage><pages>2626-2630</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Pinusolide, a labdane-type diterpene lactone isolated from Biota orientalis, was found to be a potent platelet-activating factor (PAF) receptor binding antagonist. To investigate the structure−activity relationship and find derivatives with improved pharmacological profiles, 17 pinusolide derivatives were prepared and tested for their ability to inhibit the PAF receptor binding. The results demonstrated that the carboxymethyl ester group at C-19, the integrity of the α,β-unsaturated butenolide ring, and the exocyclic olefinic function of pinusolide are all necessary for its maximum PAF receptor binding inhibitory activity. Among the derivatives, the 17-nor-8-oxo derivative 8 was found to be as potent as pinusolide. The results also suggested that several derivatives warrant further pharmaceutical and pharmacological studies due to their improved water solubility (8 and 11) and apparent lack of susceptibility to Michael-type nucleophilic addition (13 and 18).</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9651167</pmid><doi>10.1021/jm970569j</doi><tpages>5</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1998-07, Vol.41 (14), p.2626-2630 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Biological and medical sciences Blood Platelets - drug effects Blood Platelets - metabolism Blood. Blood coagulation. Reticuloendothelial system Diterpenes - chemical synthesis Diterpenes - chemistry Diterpenes - pharmacology In Vitro Techniques Medical sciences Pharmacology. Drug treatments Platelet Activating Factor - metabolism Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - chemistry Platelet Aggregation Inhibitors - pharmacology Platelet Membrane Glycoproteins - antagonists & inhibitors Rabbits Receptors, Cell Surface Receptors, G-Protein-Coupled Structure-Activity Relationship |
| title | In Vitro Platelet-Activating Factor Receptor Binding Inhibitory Activity of Pinusolide Derivatives: A Structure−Activity Study |
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