Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors
Blockade of the Na+/H+ exchange has been shown to diminish the serious consequences of myocardial ischemia. The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused...
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Veröffentlicht in: | Journal of medicinal chemistry 1998-09, Vol.41 (19), p.3736-3747 |
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creator | Baumgarth, Manfred Beier, Norbert Gericke, Rolf |
description | Blockade of the Na+/H+ exchange has been shown to diminish the serious consequences of myocardial ischemia. The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused five-, six-, and seven-membered ring sulfones were prepared by internal Heck reaction. Benz-fused five-membered ring sulfones could also be prepared by internal aldol-type condensation using ketones or nitriles as acceptor groups. In the final step, the carboxyl groups were converted to acylguanidines preferentially by guanidine treatment of the esters or acid chlorides. The compounds were tested as their methanesulfonate salts. The inhibition of the Na+/H+ antiport activity was determined by observing the uptake of 22Na+ into acidified rabbit erythrocytes. Additionally, the inhibition of the antiport activity was assessed also by the platelet swelling assay (PSA), in which the swelling of human platelets was induced by the incubation in the presence of a weak organic acid. On average, the IC50 values in the PSA turned out to be about 10-fold higher than in the erythrocyte assay primarily due to a higher Na+ concentration in the PSA; however, the order of the compounds' potency was not substantially altered. The new compounds were found to be highly active with peak values ranging within the cariporide and EMD 96785 standards. |
doi_str_mv | 10.1021/jm981031w |
format | Article |
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The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused five-, six-, and seven-membered ring sulfones were prepared by internal Heck reaction. Benz-fused five-membered ring sulfones could also be prepared by internal aldol-type condensation using ketones or nitriles as acceptor groups. In the final step, the carboxyl groups were converted to acylguanidines preferentially by guanidine treatment of the esters or acid chlorides. The compounds were tested as their methanesulfonate salts. The inhibition of the Na+/H+ antiport activity was determined by observing the uptake of 22Na+ into acidified rabbit erythrocytes. Additionally, the inhibition of the antiport activity was assessed also by the platelet swelling assay (PSA), in which the swelling of human platelets was induced by the incubation in the presence of a weak organic acid. On average, the IC50 values in the PSA turned out to be about 10-fold higher than in the erythrocyte assay primarily due to a higher Na+ concentration in the PSA; however, the order of the compounds' potency was not substantially altered. The new compounds were found to be highly active with peak values ranging within the cariporide and EMD 96785 standards.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm981031w</identifier><identifier>PMID: 9733499</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antiarythmic agents ; Biological and medical sciences ; Blood Platelets - cytology ; Blood Platelets - drug effects ; Cardiovascular system ; Cell Size - drug effects ; Erythrocytes - drug effects ; Erythrocytes - metabolism ; Guanidines - chemical synthesis ; Guanidines - chemistry ; Guanidines - pharmacology ; Humans ; In Vitro Techniques ; Medical sciences ; Pharmacology. Drug treatments ; Rabbits ; Sodium - metabolism ; Sodium-Hydrogen Exchangers - antagonists & inhibitors ; Structure-Activity Relationship ; Sulfones - pharmacology</subject><ispartof>Journal of medicinal chemistry, 1998-09, Vol.41 (19), p.3736-3747</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a377t-4c534f055fc5de6692f32ee9e9cae4cbb524e16ce1913e3c64d7ec7dab1c7f5c3</citedby><cites>FETCH-LOGICAL-a377t-4c534f055fc5de6692f32ee9e9cae4cbb524e16ce1913e3c64d7ec7dab1c7f5c3</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/jm981031w$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm981031w$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2404348$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9733499$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Baumgarth, Manfred</creatorcontrib><creatorcontrib>Beier, Norbert</creatorcontrib><creatorcontrib>Gericke, Rolf</creatorcontrib><title>Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Blockade of the Na+/H+ exchange has been shown to diminish the serious consequences of myocardial ischemia. The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused five-, six-, and seven-membered ring sulfones were prepared by internal Heck reaction. Benz-fused five-membered ring sulfones could also be prepared by internal aldol-type condensation using ketones or nitriles as acceptor groups. In the final step, the carboxyl groups were converted to acylguanidines preferentially by guanidine treatment of the esters or acid chlorides. The compounds were tested as their methanesulfonate salts. The inhibition of the Na+/H+ antiport activity was determined by observing the uptake of 22Na+ into acidified rabbit erythrocytes. Additionally, the inhibition of the antiport activity was assessed also by the platelet swelling assay (PSA), in which the swelling of human platelets was induced by the incubation in the presence of a weak organic acid. On average, the IC50 values in the PSA turned out to be about 10-fold higher than in the erythrocyte assay primarily due to a higher Na+ concentration in the PSA; however, the order of the compounds' potency was not substantially altered. The new compounds were found to be highly active with peak values ranging within the cariporide and EMD 96785 standards.</description><subject>Animals</subject><subject>Antiarythmic agents</subject><subject>Biological and medical sciences</subject><subject>Blood Platelets - cytology</subject><subject>Blood Platelets - drug effects</subject><subject>Cardiovascular system</subject><subject>Cell Size - drug effects</subject><subject>Erythrocytes - drug effects</subject><subject>Erythrocytes - metabolism</subject><subject>Guanidines - chemical synthesis</subject><subject>Guanidines - chemistry</subject><subject>Guanidines - pharmacology</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Rabbits</subject><subject>Sodium - metabolism</subject><subject>Sodium-Hydrogen Exchangers - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Sulfones - pharmacology</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>eNpt0EtLw0AUBeBBFK2PhT9A6EIFkei8ksksa32V1geo62Fyc6NT06TOJGj_vZGWrlzdxfk4XA4hh4xeMMrZ5XSmU0YF-94gPRZzGsmUyk3So5TziCdc7JDdEKaUdoaLbbKtlRBS6x4RVw4WUDroD2BRvre2crmrsP9ozy_vz_uDqnHz2jfo-6Pqw2WuqX3YJ1uFLQMerO4eebu9eR3eR5Onu9FwMImsUKqJJMRCFjSOC4hzTBLNC8ERNWqwKCHLYi6RJYBMM4ECEpkrBJXbjIEqYhB75HTZO_f1V4uhMTMXAMvSVli3wSiR6oQx3cGzJQRfh-CxMHPvZtYvDKPmbyCzHqizR6vSNpthvparRbr8eJXbALYsvK3AhTXjkkoh045FS-ZCgz_r2PpPkyihYvP6_GLYZMxT-jA2150_WXoLwUzr1lfdcv-89wvFgIdy</recordid><startdate>19980910</startdate><enddate>19980910</enddate><creator>Baumgarth, Manfred</creator><creator>Beier, Norbert</creator><creator>Gericke, Rolf</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>19980910</creationdate><title>Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors</title><author>Baumgarth, Manfred ; Beier, Norbert ; Gericke, Rolf</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a377t-4c534f055fc5de6692f32ee9e9cae4cbb524e16ce1913e3c64d7ec7dab1c7f5c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Antiarythmic agents</topic><topic>Biological and medical sciences</topic><topic>Blood Platelets - cytology</topic><topic>Blood Platelets - drug effects</topic><topic>Cardiovascular system</topic><topic>Cell Size - drug effects</topic><topic>Erythrocytes - drug effects</topic><topic>Erythrocytes - metabolism</topic><topic>Guanidines - chemical synthesis</topic><topic>Guanidines - chemistry</topic><topic>Guanidines - pharmacology</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Rabbits</topic><topic>Sodium - metabolism</topic><topic>Sodium-Hydrogen Exchangers - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Sulfones - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Baumgarth, Manfred</creatorcontrib><creatorcontrib>Beier, Norbert</creatorcontrib><creatorcontrib>Gericke, Rolf</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>Baumgarth, Manfred</au><au>Beier, Norbert</au><au>Gericke, Rolf</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-09-10</date><risdate>1998</risdate><volume>41</volume><issue>19</issue><spage>3736</spage><epage>3747</epage><pages>3736-3747</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Blockade of the Na+/H+ exchange has been shown to diminish the serious consequences of myocardial ischemia. The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused five-, six-, and seven-membered ring sulfones were prepared by internal Heck reaction. Benz-fused five-membered ring sulfones could also be prepared by internal aldol-type condensation using ketones or nitriles as acceptor groups. In the final step, the carboxyl groups were converted to acylguanidines preferentially by guanidine treatment of the esters or acid chlorides. The compounds were tested as their methanesulfonate salts. The inhibition of the Na+/H+ antiport activity was determined by observing the uptake of 22Na+ into acidified rabbit erythrocytes. Additionally, the inhibition of the antiport activity was assessed also by the platelet swelling assay (PSA), in which the swelling of human platelets was induced by the incubation in the presence of a weak organic acid. On average, the IC50 values in the PSA turned out to be about 10-fold higher than in the erythrocyte assay primarily due to a higher Na+ concentration in the PSA; however, the order of the compounds' potency was not substantially altered. The new compounds were found to be highly active with peak values ranging within the cariporide and EMD 96785 standards.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9733499</pmid><doi>10.1021/jm981031w</doi><tpages>12</tpages></addata></record> |
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subjects | Animals Antiarythmic agents Biological and medical sciences Blood Platelets - cytology Blood Platelets - drug effects Cardiovascular system Cell Size - drug effects Erythrocytes - drug effects Erythrocytes - metabolism Guanidines - chemical synthesis Guanidines - chemistry Guanidines - pharmacology Humans In Vitro Techniques Medical sciences Pharmacology. Drug treatments Rabbits Sodium - metabolism Sodium-Hydrogen Exchangers - antagonists & inhibitors Structure-Activity Relationship Sulfones - pharmacology |
title | Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors |
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