Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones
A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone (compound 35, LY255283). Using an assay for inhibition of specific [3H]LTB4 binding to human PM...
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| Veröffentlicht in: | Journal of medicinal chemistry 1992-05, Vol.35 (10), p.1818-1828 |
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| container_end_page | 1828 |
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| container_issue | 10 |
| container_start_page | 1818 |
| container_title | Journal of medicinal chemistry |
| container_volume | 35 |
| creator | Herron, David K Goodson, Theodore Bollinger, Nancy G Swanson-Bean, Dorothy Wright, Ian G Staten, Gilbert S Thompson, Alan R Froelich, Larry L Jackson, William T |
| description | A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone (compound 35, LY255283). Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity. Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function. Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation. |
| doi_str_mv | 10.1021/jm00088a018 |
| format | Article |
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Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity. Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function. Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00088a018</identifier><identifier>PMID: 1316967</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Acetophenones - metabolism ; Acetophenones - pharmacology ; Chemistry ; Exact sciences and technology ; Humans ; Leukotriene B4 - antagonists & inhibitors ; Leukotriene B4 - metabolism ; Magnetic Resonance Spectroscopy ; Neutrophils - metabolism ; Noncondensed benzenic compounds ; Organic chemistry ; Preparations and properties ; Receptors, Immunologic - antagonists & inhibitors ; Receptors, Leukotriene B4 ; Structure-Activity Relationship ; Tetrazoles - chemistry ; Tetrazoles - metabolism ; Tetrazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 1992-05, Vol.35 (10), p.1818-1828</ispartof><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a383t-e0ac9f5aa408ab73a5c7c100e00f6651555a72faaf3fe33133529beee2ebc743</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/jm00088a018$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00088a018$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27078,27926,27927,56740,56790</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5351685$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1316967$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Herron, David K</creatorcontrib><creatorcontrib>Goodson, Theodore</creatorcontrib><creatorcontrib>Bollinger, Nancy G</creatorcontrib><creatorcontrib>Swanson-Bean, Dorothy</creatorcontrib><creatorcontrib>Wright, Ian G</creatorcontrib><creatorcontrib>Staten, Gilbert S</creatorcontrib><creatorcontrib>Thompson, Alan R</creatorcontrib><creatorcontrib>Froelich, Larry L</creatorcontrib><creatorcontrib>Jackson, William T</creatorcontrib><title>Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone (compound 35, LY255283). Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity. Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function. Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.</description><subject>Acetophenones - metabolism</subject><subject>Acetophenones - pharmacology</subject><subject>Chemistry</subject><subject>Exact sciences and technology</subject><subject>Humans</subject><subject>Leukotriene B4 - antagonists & inhibitors</subject><subject>Leukotriene B4 - metabolism</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Neutrophils - metabolism</subject><subject>Noncondensed benzenic compounds</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Receptors, Immunologic - antagonists & inhibitors</subject><subject>Receptors, Leukotriene B4</subject><subject>Structure-Activity Relationship</subject><subject>Tetrazoles - chemistry</subject><subject>Tetrazoles - metabolism</subject><subject>Tetrazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MFP2zAUBnALgVhhnDgj5YDGYQp7tuPE4TbQCkgVsNHDdrJezfOa0sbFTiT6389TKrYDp3f4fvr09DF2zOGcg-BfFisA0BqB6x024kpAXmgodtkIQIhclEJ-YAcxLhKTXMh9ts8lL-uyGrGHCfXPvgsNtZRdFlkgS-vOhwzbDn_7toldvMi6OWWTX0IpoWUWKemYeZfNN0_Bv27QUufXc2p9S_Ej23O4jHS0vYdsOv42vbrJJ_fXt1dfJzlKLbucAG3tFGIBGmeVRGUrywEIwJWl4koprIRDdNKRlFxKJeoZEQma2aqQh-zTULsO_qWn2JlVEy0tl9iS76OpRF2UWtYJfh6gDT7GQM6sQ7PCsDEczN_5zH_zJX2yre1nK3r6Z4e9Un66zTFaXLqArW3iG1NS8VKrxPKBpfno9S3G8GxSSaXM9OHR_FDjn3x89908Jn82eLTRLHwf2jTduw_-AQoEkn4</recordid><startdate>19920501</startdate><enddate>19920501</enddate><creator>Herron, David K</creator><creator>Goodson, Theodore</creator><creator>Bollinger, Nancy G</creator><creator>Swanson-Bean, Dorothy</creator><creator>Wright, Ian G</creator><creator>Staten, Gilbert S</creator><creator>Thompson, Alan R</creator><creator>Froelich, Larry L</creator><creator>Jackson, William T</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>19920501</creationdate><title>Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones</title><author>Herron, David K ; Goodson, Theodore ; Bollinger, Nancy G ; Swanson-Bean, Dorothy ; Wright, Ian G ; Staten, Gilbert S ; Thompson, Alan R ; Froelich, Larry L ; Jackson, William T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-e0ac9f5aa408ab73a5c7c100e00f6651555a72faaf3fe33133529beee2ebc743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Acetophenones - metabolism</topic><topic>Acetophenones - pharmacology</topic><topic>Chemistry</topic><topic>Exact sciences and technology</topic><topic>Humans</topic><topic>Leukotriene B4 - antagonists & inhibitors</topic><topic>Leukotriene B4 - metabolism</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Neutrophils - metabolism</topic><topic>Noncondensed benzenic compounds</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Receptors, Immunologic - antagonists & inhibitors</topic><topic>Receptors, Leukotriene B4</topic><topic>Structure-Activity Relationship</topic><topic>Tetrazoles - chemistry</topic><topic>Tetrazoles - metabolism</topic><topic>Tetrazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Herron, David K</creatorcontrib><creatorcontrib>Goodson, Theodore</creatorcontrib><creatorcontrib>Bollinger, Nancy G</creatorcontrib><creatorcontrib>Swanson-Bean, Dorothy</creatorcontrib><creatorcontrib>Wright, Ian G</creatorcontrib><creatorcontrib>Staten, Gilbert S</creatorcontrib><creatorcontrib>Thompson, Alan R</creatorcontrib><creatorcontrib>Froelich, Larry L</creatorcontrib><creatorcontrib>Jackson, William T</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>Herron, David K</au><au>Goodson, Theodore</au><au>Bollinger, Nancy G</au><au>Swanson-Bean, Dorothy</au><au>Wright, Ian G</au><au>Staten, Gilbert S</au><au>Thompson, Alan R</au><au>Froelich, Larry L</au><au>Jackson, William T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1992-05-01</date><risdate>1992</risdate><volume>35</volume><issue>10</issue><spage>1818</spage><epage>1828</epage><pages>1818-1828</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone (compound 35, LY255283). Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity. Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function. Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>1316967</pmid><doi>10.1021/jm00088a018</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1992-05, Vol.35 (10), p.1818-1828 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Acetophenones - metabolism Acetophenones - pharmacology Chemistry Exact sciences and technology Humans Leukotriene B4 - antagonists & inhibitors Leukotriene B4 - metabolism Magnetic Resonance Spectroscopy Neutrophils - metabolism Noncondensed benzenic compounds Organic chemistry Preparations and properties Receptors, Immunologic - antagonists & inhibitors Receptors, Leukotriene B4 Structure-Activity Relationship Tetrazoles - chemistry Tetrazoles - metabolism Tetrazoles - pharmacology |
| title | Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones |
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