Synthesis and antiarrhythmic activity of new 3-[2-(.omega.-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds
A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an e...
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| Veröffentlicht in: | Journal of medicinal chemistry 1987-05, Vol.30 (5), p.773-780 |
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| container_end_page | 780 |
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| container_issue | 5 |
| container_start_page | 773 |
| container_title | Journal of medicinal chemistry |
| container_volume | 30 |
| creator | Salimbeni, Aldo Manghisi, Elso Fregnan, Giancarlo B Prada, Marco |
| description | A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation. |
| doi_str_mv | 10.1021/jm00388a005 |
| format | Article |
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The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00388a005</identifier><identifier>PMID: 3572966</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amines - chemical synthesis ; Amines - therapeutic use ; Amines - toxicity ; Animals ; Arrhythmias, Cardiac - drug therapy ; Chemical Phenomena ; Chemistry ; Dogs ; Exact sciences and technology ; Female ; Lethal Dose 50 ; Male ; Mice ; Noncondensed benzenic compounds ; Organic chemistry ; Phenyl Ethers - chemical synthesis ; Phenyl Ethers - therapeutic use ; Phenyl Ethers - toxicity ; Preparations and properties ; Procainamide - therapeutic use ; Quinidine - therapeutic use ; Rabbits ; Rats ; Rats, Inbred Strains ; Structure-Activity Relationship ; Ventricular Fibrillation - drug therapy</subject><ispartof>Journal of medicinal chemistry, 1987-05, Vol.30 (5), p.773-780</ispartof><rights>1987 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a383t-7fdd9d3037dd34922b37b17dd34fbb06159e4f4a527360531bcb04b21b3ad8223</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/jm00388a005$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00388a005$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=8325830$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3572966$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Salimbeni, Aldo</creatorcontrib><creatorcontrib>Manghisi, Elso</creatorcontrib><creatorcontrib>Fregnan, Giancarlo B</creatorcontrib><creatorcontrib>Prada, Marco</creatorcontrib><title>Synthesis and antiarrhythmic activity of new 3-[2-(.omega.-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.</description><subject>Amines - chemical synthesis</subject><subject>Amines - therapeutic use</subject><subject>Amines - toxicity</subject><subject>Animals</subject><subject>Arrhythmias, Cardiac - drug therapy</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Dogs</subject><subject>Exact sciences and technology</subject><subject>Female</subject><subject>Lethal Dose 50</subject><subject>Male</subject><subject>Mice</subject><subject>Noncondensed benzenic compounds</subject><subject>Organic chemistry</subject><subject>Phenyl Ethers - chemical synthesis</subject><subject>Phenyl Ethers - therapeutic use</subject><subject>Phenyl Ethers - toxicity</subject><subject>Preparations and properties</subject><subject>Procainamide - therapeutic use</subject><subject>Quinidine - therapeutic use</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Structure-Activity Relationship</subject><subject>Ventricular Fibrillation - drug therapy</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1987</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkN1rFDEUxYNY6nb1yWdhHgQrJWuSO5-PUqxWChZaQRAJN5OMm-1MsiRZ7Tz4vzvtLIsPPlzOvZwfl8Mh5CVnK84Ef7cZGIO6RsaKJ2TBC8FoXrP8KVkwJgQVpYBn5CTGDZs4LuCYHENRiaYsF-TPzejS2kQbM3R6mmQxhPWY1oNtM2yT_WXTmPkuc-Z3BvS7oKcrP5ifuKI4WOexv_P349vt2rhJf9CcPqxjT4GqXTKOCuqdmb8H02MyOmv9sPU7p-NzctRhH82LvS7J14sPt-ef6NWXj5fn768oQg2JVp3WjQYGldaQN0IoqBR_PDqlWMmLxuRdjoWooGQFcNUqlivBFaCuhYAlOZv_tsHHGEwnt8EOGEbJmXzoUP7T4US_muntTg1GH9h9aZP_eu9jbLHvArrWxgNWgyjqKeyS0BmzMZn7g43hTpYVVIW8vb6Rn3ldNfzim7ye-Dczj22UG78LbqrkvwH_Ar2MlMg</recordid><startdate>19870501</startdate><enddate>19870501</enddate><creator>Salimbeni, Aldo</creator><creator>Manghisi, Elso</creator><creator>Fregnan, Giancarlo B</creator><creator>Prada, Marco</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></search><sort><creationdate>19870501</creationdate><title>Synthesis and antiarrhythmic activity of new 3-[2-(.omega.-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds</title><author>Salimbeni, Aldo ; Manghisi, Elso ; Fregnan, Giancarlo B ; Prada, Marco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-7fdd9d3037dd34922b37b17dd34fbb06159e4f4a527360531bcb04b21b3ad8223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1987</creationdate><topic>Amines - chemical synthesis</topic><topic>Amines - therapeutic use</topic><topic>Amines - toxicity</topic><topic>Animals</topic><topic>Arrhythmias, Cardiac - drug therapy</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Dogs</topic><topic>Exact sciences and technology</topic><topic>Female</topic><topic>Lethal Dose 50</topic><topic>Male</topic><topic>Mice</topic><topic>Noncondensed benzenic compounds</topic><topic>Organic chemistry</topic><topic>Phenyl Ethers - chemical synthesis</topic><topic>Phenyl Ethers - therapeutic use</topic><topic>Phenyl Ethers - toxicity</topic><topic>Preparations and properties</topic><topic>Procainamide - therapeutic use</topic><topic>Quinidine - therapeutic use</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Structure-Activity Relationship</topic><topic>Ventricular Fibrillation - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salimbeni, Aldo</creatorcontrib><creatorcontrib>Manghisi, Elso</creatorcontrib><creatorcontrib>Fregnan, Giancarlo B</creatorcontrib><creatorcontrib>Prada, Marco</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Salimbeni, Aldo</au><au>Manghisi, Elso</au><au>Fregnan, Giancarlo B</au><au>Prada, Marco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and antiarrhythmic activity of new 3-[2-(.omega.-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1987-05-01</date><risdate>1987</risdate><volume>30</volume><issue>5</issue><spage>773</spage><epage>780</epage><pages>773-780</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>3572966</pmid><doi>10.1021/jm00388a005</doi><tpages>8</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1987-05, Vol.30 (5), p.773-780 |
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| source | MEDLINE; ACS Publications |
| subjects | Amines - chemical synthesis Amines - therapeutic use Amines - toxicity Animals Arrhythmias, Cardiac - drug therapy Chemical Phenomena Chemistry Dogs Exact sciences and technology Female Lethal Dose 50 Male Mice Noncondensed benzenic compounds Organic chemistry Phenyl Ethers - chemical synthesis Phenyl Ethers - therapeutic use Phenyl Ethers - toxicity Preparations and properties Procainamide - therapeutic use Quinidine - therapeutic use Rabbits Rats Rats, Inbred Strains Structure-Activity Relationship Ventricular Fibrillation - drug therapy |
| title | Synthesis and antiarrhythmic activity of new 3-[2-(.omega.-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds |
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