Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors
The discovery and optimization of a benzenesulfonanilide series of 11β-HSD1 inhibitors is reported. A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitr...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-06, Vol.22 (11), p.3786-3790 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Rew, Yosup DeGraffenreid, Michael He, Xiao Jaen, Juan C. McMinn, Dustin L. Sun, Daqing Tu, Hua Ursu, Stefania Powers, Jay P. |
| description | The discovery and optimization of a benzenesulfonanilide series of 11β-HSD1 inhibitors is reported.
A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure–activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC50=1.8 and 1.4nM, respectively). |
| doi_str_mv | 10.1016/j.bmcl.2012.04.005 |
| format | Article |
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A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure–activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC50=1.8 and 1.4nM, respectively).</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.04.005</identifier><identifier>PMID: 22542009</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism ; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - pharmacology ; 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor ; alcohol oxidoreductases ; Anilides - chemical synthesis ; Anilides - chemistry ; Aniline Compounds - chemical synthesis ; Aniline Compounds - chemistry ; Aniline Compounds - pharmacology ; Benzenesulfonanilide ; Biological and medical sciences ; Crystallography, X-Ray ; Drug Evaluation, Preclinical ; Enzyme Activation - drug effects ; enzyme inhibitors ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; HEK293 Cells ; Humans ; in vitro studies ; Medical sciences ; Molecular Conformation ; Pharmacology. Drug treatments ; Piperazines - chemical synthesis ; Piperazines - chemistry ; Piperazines - pharmacology ; Structure-Activity Relationship ; structure-activity relationships ; Sulfonamides - chemical synthesis ; Sulfonamides - chemistry ; Sulfonamides - pharmacology ; system optimization ; Transfection</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-06, Vol.22 (11), p.3786-3790</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-bf905ec62781d2b2f0c3e2db01a73715a91794f313f90b9ee108f865d60f0e0a3</citedby><cites>FETCH-LOGICAL-c410t-bf905ec62781d2b2f0c3e2db01a73715a91794f313f90b9ee108f865d60f0e0a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X12004441$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25943956$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22542009$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rew, Yosup</creatorcontrib><creatorcontrib>DeGraffenreid, Michael</creatorcontrib><creatorcontrib>He, Xiao</creatorcontrib><creatorcontrib>Jaen, Juan C.</creatorcontrib><creatorcontrib>McMinn, Dustin L.</creatorcontrib><creatorcontrib>Sun, Daqing</creatorcontrib><creatorcontrib>Tu, Hua</creatorcontrib><creatorcontrib>Ursu, Stefania</creatorcontrib><creatorcontrib>Powers, Jay P.</creatorcontrib><title>Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The discovery and optimization of a benzenesulfonanilide series of 11β-HSD1 inhibitors is reported.
A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure–activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC50=1.8 and 1.4nM, respectively).</description><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors</subject><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics</subject><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism</subject><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - pharmacology</subject><subject>11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor</subject><subject>alcohol oxidoreductases</subject><subject>Anilides - chemical synthesis</subject><subject>Anilides - chemistry</subject><subject>Aniline Compounds - chemical synthesis</subject><subject>Aniline Compounds - chemistry</subject><subject>Aniline Compounds - pharmacology</subject><subject>Benzenesulfonanilide</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Drug Evaluation, Preclinical</subject><subject>Enzyme Activation - drug effects</subject><subject>enzyme inhibitors</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>in vitro studies</subject><subject>Medical sciences</subject><subject>Molecular Conformation</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><subject>system optimization</subject><subject>Transfection</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90cFu1DAQBmALgehSeAEOkAsSl4SxYydriUvV0hapEodSiZvlOOPilWMvdnal9rF4EJ4JR7vADcmSL9-MZ34T8ppCQ4F2HzbNMBnfMKCsAd4AiCdkRXnH65aDeEpWIDuo15J_OyEvct4AUA6cPycnjAnOAOSK3F-4bOIe00Olw1jF7ewm96hnF0MVbTVgeMSAeedtDDo470asRkxuX8gec6XLqUJp4Cvjdc5LEaW_ftbXtxe0cuG7G9wcU35JnlntM7463qfk7vLT1_Pr-ubL1efzs5vacApzPVgJAk3H-jUd2cAsmBbZOADVfdtToSXtJbctbQscJCKFtV13YuzAAoJuT8n7Q99tij92mGc1lQXRex0w7rIqwbWSUSagUHagJsWcE1q1TW7S6aGgxXVqo5aA1RKwAq5KwKXozbH_bphw_FvyJ9EC3h2BzkZ7m3QwLv9zQvJWiq64twdndVT6PhVzd1teEuWXWujpMt_Hg8CS195hUtk4DAZHl9DMaozuf5P-BiBzowo</recordid><startdate>20120601</startdate><enddate>20120601</enddate><creator>Rew, Yosup</creator><creator>DeGraffenreid, Michael</creator><creator>He, Xiao</creator><creator>Jaen, Juan C.</creator><creator>McMinn, Dustin L.</creator><creator>Sun, Daqing</creator><creator>Tu, Hua</creator><creator>Ursu, Stefania</creator><creator>Powers, Jay P.</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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>20120601</creationdate><title>Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors</title><author>Rew, Yosup ; DeGraffenreid, Michael ; He, Xiao ; Jaen, Juan C. ; McMinn, Dustin L. ; Sun, Daqing ; Tu, Hua ; Ursu, Stefania ; Powers, Jay P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-bf905ec62781d2b2f0c3e2db01a73715a91794f313f90b9ee108f865d60f0e0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors</topic><topic>11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics</topic><topic>11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism</topic><topic>11-beta-Hydroxysteroid Dehydrogenase Type 1 - pharmacology</topic><topic>11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor</topic><topic>alcohol oxidoreductases</topic><topic>Anilides - chemical synthesis</topic><topic>Anilides - chemistry</topic><topic>Aniline Compounds - chemical synthesis</topic><topic>Aniline Compounds - chemistry</topic><topic>Aniline Compounds - pharmacology</topic><topic>Benzenesulfonanilide</topic><topic>Biological and medical sciences</topic><topic>Crystallography, X-Ray</topic><topic>Drug Evaluation, Preclinical</topic><topic>Enzyme Activation - drug effects</topic><topic>enzyme inhibitors</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>in vitro studies</topic><topic>Medical sciences</topic><topic>Molecular Conformation</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><topic>system optimization</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rew, Yosup</creatorcontrib><creatorcontrib>DeGraffenreid, Michael</creatorcontrib><creatorcontrib>He, Xiao</creatorcontrib><creatorcontrib>Jaen, Juan C.</creatorcontrib><creatorcontrib>McMinn, Dustin L.</creatorcontrib><creatorcontrib>Sun, Daqing</creatorcontrib><creatorcontrib>Tu, Hua</creatorcontrib><creatorcontrib>Ursu, Stefania</creatorcontrib><creatorcontrib>Powers, Jay P.</creatorcontrib><collection>AGRIS</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rew, Yosup</au><au>DeGraffenreid, Michael</au><au>He, Xiao</au><au>Jaen, Juan C.</au><au>McMinn, Dustin L.</au><au>Sun, Daqing</au><au>Tu, Hua</au><au>Ursu, Stefania</au><au>Powers, Jay P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-06-01</date><risdate>2012</risdate><volume>22</volume><issue>11</issue><spage>3786</spage><epage>3790</epage><pages>3786-3790</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The discovery and optimization of a benzenesulfonanilide series of 11β-HSD1 inhibitors is reported.
A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure–activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC50=1.8 and 1.4nM, respectively).</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22542009</pmid><doi>10.1016/j.bmcl.2012.04.005</doi><tpages>5</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-06, Vol.22 (11), p.3786-3790 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism 11-beta-Hydroxysteroid Dehydrogenase Type 1 - pharmacology 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor alcohol oxidoreductases Anilides - chemical synthesis Anilides - chemistry Aniline Compounds - chemical synthesis Aniline Compounds - chemistry Aniline Compounds - pharmacology Benzenesulfonanilide Biological and medical sciences Crystallography, X-Ray Drug Evaluation, Preclinical Enzyme Activation - drug effects enzyme inhibitors Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HEK293 Cells Humans in vitro studies Medical sciences Molecular Conformation Pharmacology. Drug treatments Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Structure-Activity Relationship structure-activity relationships Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology system optimization Transfection |
| title | Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors |
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