Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides
The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Comp...
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| Veröffentlicht in: | Journal of medicinal chemistry 1992-02, Vol.35 (4), p.705-716 |
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| container_end_page | 716 |
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| container_issue | 4 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 35 |
| creator | Ellingboe, John W Spinelli, Walter Winkley, Michael W Nguyen, Thomas T Parsons, Roderick W Moubarak, Issam F Kitzen, Jan M Von Engen, Donna Bagli, Jehan F |
| description | The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration. |
| doi_str_mv | 10.1021/jm00082a011 |
| format | Article |
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Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00082a011</identifier><identifier>PMID: 1542097</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Action Potentials - drug effects ; Anti-Arrhythmia Agents - chemical synthesis ; Anti-Arrhythmia Agents - pharmacology ; Anti-Arrhythmia Agents - therapeutic use ; Atrial Function ; Benzamides - chemistry ; Benzamides - pharmacology ; Benzimidazoles - chemical synthesis ; Benzimidazoles - pharmacology ; Benzimidazoles - therapeutic use ; Biological Availability ; Chemistry ; Condensed matter: structure, mechanical and thermal properties ; Electric Conductivity ; Exact sciences and technology ; Heart Atria - drug effects ; Heart Conduction System - drug effects ; Heart Conduction System - physiology ; Heart Ventricles - drug effects ; Heterocyclic compounds ; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings ; Membrane Potentials - drug effects ; Molecular Structure ; Myocardial Contraction - drug effects ; Organic chemistry ; Organic compounds ; Physics ; Preparations and properties ; Purkinje Fibers - drug effects ; Purkinje Fibers - physiology ; Structure of solids and liquids; crystallography ; Structure of specific crystalline solids ; Structure-Activity Relationship ; Sulfanilamides - chemical synthesis ; Sulfanilamides - pharmacology ; Sulfanilamides - therapeutic use ; Sulfonamides - chemistry ; Sulfonamides - pharmacology ; Ventricular Fibrillation - drug therapy ; Ventricular Function</subject><ispartof>Journal of medicinal chemistry, 1992-02, Vol.35 (4), p.705-716</ispartof><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-b0df1f4c391914337ffe4e7a19510bb62b60bf699293e8b9e7fbe1afbe1515bd3</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/jm00082a011$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00082a011$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5204692$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1542097$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ellingboe, John W</creatorcontrib><creatorcontrib>Spinelli, Walter</creatorcontrib><creatorcontrib>Winkley, Michael W</creatorcontrib><creatorcontrib>Nguyen, Thomas T</creatorcontrib><creatorcontrib>Parsons, Roderick W</creatorcontrib><creatorcontrib>Moubarak, Issam F</creatorcontrib><creatorcontrib>Kitzen, Jan M</creatorcontrib><creatorcontrib>Von Engen, Donna</creatorcontrib><creatorcontrib>Bagli, Jehan F</creatorcontrib><title>Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.</description><subject>Action Potentials - drug effects</subject><subject>Anti-Arrhythmia Agents - chemical synthesis</subject><subject>Anti-Arrhythmia Agents - pharmacology</subject><subject>Anti-Arrhythmia Agents - therapeutic use</subject><subject>Atrial Function</subject><subject>Benzamides - chemistry</subject><subject>Benzamides - pharmacology</subject><subject>Benzimidazoles - chemical synthesis</subject><subject>Benzimidazoles - pharmacology</subject><subject>Benzimidazoles - therapeutic use</subject><subject>Biological Availability</subject><subject>Chemistry</subject><subject>Condensed matter: structure, mechanical and thermal properties</subject><subject>Electric Conductivity</subject><subject>Exact sciences and technology</subject><subject>Heart Atria - drug effects</subject><subject>Heart Conduction System - drug effects</subject><subject>Heart Conduction System - physiology</subject><subject>Heart Ventricles - drug effects</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</subject><subject>Membrane Potentials - drug effects</subject><subject>Molecular Structure</subject><subject>Myocardial Contraction - drug effects</subject><subject>Organic chemistry</subject><subject>Organic compounds</subject><subject>Physics</subject><subject>Preparations and properties</subject><subject>Purkinje Fibers - drug effects</subject><subject>Purkinje Fibers - physiology</subject><subject>Structure of solids and liquids; crystallography</subject><subject>Structure of specific crystalline solids</subject><subject>Structure-Activity Relationship</subject><subject>Sulfanilamides - chemical synthesis</subject><subject>Sulfanilamides - pharmacology</subject><subject>Sulfanilamides - therapeutic use</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><subject>Ventricular Fibrillation - drug therapy</subject><subject>Ventricular Function</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>eNptkc1r3DAQxUVoSTdpTj0XfChNS3CjL9urY9kkzUKgLflooRQh2RKrjWwnGjnU_eurxUvSQy4zg96PN-INQm8I_kQwJcfrFmM8pwoTsoNmpKA453PMX6AZxpTmtKTsFdoDWCeMEcp20S4pOMWimqHbhVcA2XK5zFQXnQphNcZV6-pM1dE9uDhmvc26_sH4DAYN0cUhmibj-a8PrYmr0cPgbd-N_qNqXdf_1qb7m6bGQDJsskmdHl6jl1Z5MAfbvo-uz06vFuf5xdcvy8Xni1xxLmKucWOJ5TUTRBDOWGWt4aZSRBQEa11SXWJtSyGoYGauhamsNkRtSkEK3bB99H7yvQv9_WAgytZBbbxXnekHkBWds0pQmsCjCaxDDxCMlXfBtSqMkmC5iVb-F22i325tB92a5omdskz6u62uoFbeBtXVDh6xdBZeis3SfMIcRPPnUVbhVpYVqwp59e1S_ji5OfspToj8nvjDiVc1yHU_hC5l9-wH_wHWhZ5W</recordid><startdate>19920201</startdate><enddate>19920201</enddate><creator>Ellingboe, John W</creator><creator>Spinelli, Walter</creator><creator>Winkley, Michael W</creator><creator>Nguyen, Thomas T</creator><creator>Parsons, Roderick W</creator><creator>Moubarak, Issam F</creator><creator>Kitzen, Jan M</creator><creator>Von Engen, Donna</creator><creator>Bagli, Jehan F</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>19920201</creationdate><title>Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides</title><author>Ellingboe, John W ; Spinelli, Walter ; Winkley, Michael W ; Nguyen, Thomas T ; Parsons, Roderick W ; Moubarak, Issam F ; Kitzen, Jan M ; Von Engen, Donna ; Bagli, Jehan F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-b0df1f4c391914337ffe4e7a19510bb62b60bf699293e8b9e7fbe1afbe1515bd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Action Potentials - drug effects</topic><topic>Anti-Arrhythmia Agents - chemical synthesis</topic><topic>Anti-Arrhythmia Agents - pharmacology</topic><topic>Anti-Arrhythmia Agents - therapeutic use</topic><topic>Atrial Function</topic><topic>Benzamides - chemistry</topic><topic>Benzamides - pharmacology</topic><topic>Benzimidazoles - chemical synthesis</topic><topic>Benzimidazoles - pharmacology</topic><topic>Benzimidazoles - therapeutic use</topic><topic>Biological Availability</topic><topic>Chemistry</topic><topic>Condensed matter: structure, mechanical and thermal properties</topic><topic>Electric Conductivity</topic><topic>Exact sciences and technology</topic><topic>Heart Atria - drug effects</topic><topic>Heart Conduction System - drug effects</topic><topic>Heart Conduction System - physiology</topic><topic>Heart Ventricles - drug effects</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</topic><topic>Membrane Potentials - drug effects</topic><topic>Molecular Structure</topic><topic>Myocardial Contraction - drug effects</topic><topic>Organic chemistry</topic><topic>Organic compounds</topic><topic>Physics</topic><topic>Preparations and properties</topic><topic>Purkinje Fibers - drug effects</topic><topic>Purkinje Fibers - physiology</topic><topic>Structure of solids and liquids; crystallography</topic><topic>Structure of specific crystalline solids</topic><topic>Structure-Activity Relationship</topic><topic>Sulfanilamides - chemical synthesis</topic><topic>Sulfanilamides - pharmacology</topic><topic>Sulfanilamides - therapeutic use</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><topic>Ventricular Fibrillation - drug therapy</topic><topic>Ventricular Function</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ellingboe, John W</creatorcontrib><creatorcontrib>Spinelli, Walter</creatorcontrib><creatorcontrib>Winkley, Michael W</creatorcontrib><creatorcontrib>Nguyen, Thomas T</creatorcontrib><creatorcontrib>Parsons, Roderick W</creatorcontrib><creatorcontrib>Moubarak, Issam F</creatorcontrib><creatorcontrib>Kitzen, Jan M</creatorcontrib><creatorcontrib>Von Engen, Donna</creatorcontrib><creatorcontrib>Bagli, Jehan F</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>Ellingboe, John W</au><au>Spinelli, Walter</au><au>Winkley, Michael W</au><au>Nguyen, Thomas T</au><au>Parsons, Roderick W</au><au>Moubarak, Issam F</au><au>Kitzen, Jan M</au><au>Von Engen, Donna</au><au>Bagli, Jehan F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1992-02-01</date><risdate>1992</risdate><volume>35</volume><issue>4</issue><spage>705</spage><epage>716</epage><pages>705-716</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>1542097</pmid><doi>10.1021/jm00082a011</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 1992-02, Vol.35 (4), p.705-716 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Action Potentials - drug effects Anti-Arrhythmia Agents - chemical synthesis Anti-Arrhythmia Agents - pharmacology Anti-Arrhythmia Agents - therapeutic use Atrial Function Benzamides - chemistry Benzamides - pharmacology Benzimidazoles - chemical synthesis Benzimidazoles - pharmacology Benzimidazoles - therapeutic use Biological Availability Chemistry Condensed matter: structure, mechanical and thermal properties Electric Conductivity Exact sciences and technology Heart Atria - drug effects Heart Conduction System - drug effects Heart Conduction System - physiology Heart Ventricles - drug effects Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Membrane Potentials - drug effects Molecular Structure Myocardial Contraction - drug effects Organic chemistry Organic compounds Physics Preparations and properties Purkinje Fibers - drug effects Purkinje Fibers - physiology Structure of solids and liquids crystallography Structure of specific crystalline solids Structure-Activity Relationship Sulfanilamides - chemical synthesis Sulfanilamides - pharmacology Sulfanilamides - therapeutic use Sulfonamides - chemistry Sulfonamides - pharmacology Ventricular Fibrillation - drug therapy Ventricular Function |
| title | Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides |
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