Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-a antagonists
We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl...
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| Veröffentlicht in: | Journal of medicinal chemistry 1997-05, Vol.40 (11), p.1682-1688 |
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| container_issue | 11 |
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| container_title | Journal of medicinal chemistry |
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| creator | WU, C CHAN, M. F STAVROS, F RAJU, B OKUN, I CASTILLO, R. S |
| description | We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl being preferred. With disubstitution, 2,4-disubstitution further enhanced activity with methyl or cyano groups being preferred at the 2-position. In this series, a benzo-[d][1,3]dioxole group is equivalent to a 4-methyl group in in vitro activity and afforded the compounds with both in vivo activity and moderate half-lives. |
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F ; STAVROS, F ; RAJU, B ; OKUN, I ; CASTILLO, R. S</creator><creatorcontrib>WU, C ; CHAN, M. F ; STAVROS, F ; RAJU, B ; OKUN, I ; CASTILLO, R. S</creatorcontrib><description>We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl being preferred. With disubstitution, 2,4-disubstitution further enhanced activity with methyl or cyano groups being preferred at the 2-position. In this series, a benzo-[d][1,3]dioxole group is equivalent to a 4-methyl group in in vitro activity and afforded the compounds with both in vivo activity and moderate half-lives.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>PMID: 9171877</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Binding, Competitive ; Biological and medical sciences ; Blood Pressure - drug effects ; Cardiovascular system ; Cell Line ; COS Cells ; Endothelin Receptor Antagonists ; Endothelin-1 - metabolism ; Endothelins - metabolism ; Half-Life ; Humans ; Hydrolysis ; Isoxazoles - chemistry ; Isoxazoles - pharmacokinetics ; Isoxazoles - pharmacology ; Male ; Medical sciences ; Molecular Structure ; Pharmacology. Drug treatments ; Phosphatidylinositols - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin A ; Receptors, Endothelin - metabolism ; Structure-Activity Relationship ; Thiophenes - chemistry ; Thiophenes - pharmacokinetics ; Thiophenes - pharmacology ; Vasodilator agents. 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S</creatorcontrib><title>Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-a antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl being preferred. With disubstitution, 2,4-disubstitution further enhanced activity with methyl or cyano groups being preferred at the 2-position. In this series, a benzo-[d][1,3]dioxole group is equivalent to a 4-methyl group in in vitro activity and afforded the compounds with both in vivo activity and moderate half-lives.</description><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Blood Pressure - drug effects</subject><subject>Cardiovascular system</subject><subject>Cell Line</subject><subject>COS Cells</subject><subject>Endothelin Receptor Antagonists</subject><subject>Endothelin-1 - metabolism</subject><subject>Endothelins - metabolism</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Isoxazoles - chemistry</subject><subject>Isoxazoles - pharmacokinetics</subject><subject>Isoxazoles - pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphatidylinositols - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Endothelin A</subject><subject>Receptors, Endothelin - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Thiophenes - chemistry</subject><subject>Thiophenes - pharmacokinetics</subject><subject>Thiophenes - pharmacology</subject><subject>Vasodilator agents. 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S</creator><general>American Chemical Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19970523</creationdate><title>Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-a antagonists</title><author>WU, C ; CHAN, M. F ; STAVROS, F ; RAJU, B ; OKUN, I ; CASTILLO, R. S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p827-c84c1e0f2c7a219bddede8532cc324b5dc19adc1c04dec3ff0c77cbc74c1235d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Blood Pressure - drug effects</topic><topic>Cardiovascular system</topic><topic>Cell Line</topic><topic>COS Cells</topic><topic>Endothelin Receptor Antagonists</topic><topic>Endothelin-1 - metabolism</topic><topic>Endothelins - metabolism</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>Isoxazoles - chemistry</topic><topic>Isoxazoles - pharmacokinetics</topic><topic>Isoxazoles - pharmacology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphatidylinositols - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor, Endothelin A</topic><topic>Receptors, Endothelin - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Thiophenes - chemistry</topic><topic>Thiophenes - pharmacokinetics</topic><topic>Thiophenes - pharmacology</topic><topic>Vasodilator agents. Cerebral vasodilators</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WU, C</creatorcontrib><creatorcontrib>CHAN, M. F</creatorcontrib><creatorcontrib>STAVROS, F</creatorcontrib><creatorcontrib>RAJU, B</creatorcontrib><creatorcontrib>OKUN, I</creatorcontrib><creatorcontrib>CASTILLO, R. S</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>WU, C</au><au>CHAN, M. F</au><au>STAVROS, F</au><au>RAJU, B</au><au>OKUN, I</au><au>CASTILLO, R. S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-a antagonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>1997-05-23</date><risdate>1997</risdate><volume>40</volume><issue>11</issue><spage>1682</spage><epage>1688</epage><pages>1682-1688</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl being preferred. With disubstitution, 2,4-disubstitution further enhanced activity with methyl or cyano groups being preferred at the 2-position. In this series, a benzo-[d][1,3]dioxole group is equivalent to a 4-methyl group in in vitro activity and afforded the compounds with both in vivo activity and moderate half-lives.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9171877</pmid><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1997-05, Vol.40 (11), p.1682-1688 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Binding, Competitive Biological and medical sciences Blood Pressure - drug effects Cardiovascular system Cell Line COS Cells Endothelin Receptor Antagonists Endothelin-1 - metabolism Endothelins - metabolism Half-Life Humans Hydrolysis Isoxazoles - chemistry Isoxazoles - pharmacokinetics Isoxazoles - pharmacology Male Medical sciences Molecular Structure Pharmacology. Drug treatments Phosphatidylinositols - metabolism Rats Rats, Sprague-Dawley Receptor, Endothelin A Receptors, Endothelin - metabolism Structure-Activity Relationship Thiophenes - chemistry Thiophenes - pharmacokinetics Thiophenes - pharmacology Vasodilator agents. Cerebral vasodilators |
| title | Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-a antagonists |
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