Optimization of N′-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket
[Display omitted] The discovery of non-basic N′-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor....
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-03, Vol.26 (6), p.1605-1611 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | van Loevezijn, Arnold Venhorst, Jennifer Iwema Bakker, Wouter I. Lange, Jos H.M. de Looff, Wouter Henzen, Remco de Vries, Jelle van de Woestijne, Rob P. den Hartog, Arnold P. Verhoog, Stefan van der Neut, Martina A.W. de Bruin, Natasja M.W.J. Kruse, Chris G. |
| description | [Display omitted]
The discovery of non-basic N′-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies. |
| doi_str_mv | 10.1016/j.bmcl.2016.02.001 |
| format | Article |
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The discovery of non-basic N′-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.02.001</identifier><identifier>PMID: 26876931</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>5-HT6 receptor ; Binding Sites - drug effects ; Dose-Response Relationship, Drug ; Humans ; Molecular Docking Simulation ; Molecular modeling ; Molecular Structure ; Non-basic 5-HT6 antagonists ; N′-(Arylsulfonyl)pyrazoline-1-carboxamidines ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Receptors, Serotonin - metabolism ; Serotonin Antagonists - chemical synthesis ; Serotonin Antagonists - chemistry ; Serotonin Antagonists - pharmacology ; Structure-Activity Relationship ; Sulfonamides - chemical synthesis ; Sulfonamides - chemistry ; Sulfonamides - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-03, Vol.26 (6), p.1605-1611</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2016.02.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26876931$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van Loevezijn, Arnold</creatorcontrib><creatorcontrib>Venhorst, Jennifer</creatorcontrib><creatorcontrib>Iwema Bakker, Wouter I.</creatorcontrib><creatorcontrib>Lange, Jos H.M.</creatorcontrib><creatorcontrib>de Looff, Wouter</creatorcontrib><creatorcontrib>Henzen, Remco</creatorcontrib><creatorcontrib>de Vries, Jelle</creatorcontrib><creatorcontrib>van de Woestijne, Rob P.</creatorcontrib><creatorcontrib>den Hartog, Arnold P.</creatorcontrib><creatorcontrib>Verhoog, Stefan</creatorcontrib><creatorcontrib>van der Neut, Martina A.W.</creatorcontrib><creatorcontrib>de Bruin, Natasja M.W.J.</creatorcontrib><creatorcontrib>Kruse, Chris G.</creatorcontrib><title>Optimization of N′-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The discovery of non-basic N′-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.</description><subject>5-HT6 receptor</subject><subject>Binding Sites - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>Molecular modeling</subject><subject>Molecular Structure</subject><subject>Non-basic 5-HT6 antagonists</subject><subject>N′-(Arylsulfonyl)pyrazoline-1-carboxamidines</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Serotonin Antagonists - chemical synthesis</subject><subject>Serotonin Antagonists - chemistry</subject><subject>Serotonin Antagonists - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kU1u1TAUhS0Eoo_CBhggD8vAwY4dx5GYoAooUkUnRWJmOfZN8cOxQ-xX9XXEClgMS-pK6kfL6P7ou0dX5yD0mtGGUSbfbZtxtqFpa9_QtqGUPUEbJqQgXNDuKdrQQVKiBvH9CL3IeVsBQYV4jo5aqXo5cLZBfy6W4md_a4pPEacJf737_ZecmHUf8i5MKe7D22W_mtsUfATCiDXrmG7M7F2dMx73GG6WkHzx8QobHNM1BOxjgdXYf5rZF6gLXH4A7sjZpcQmFnOVos_FWzz66A6nS7I_obxEzyYTMrx6rMfo26ePl6dn5Pzi85fTD-cE2CAKaZ2zE2WdYFRJ1XVGjePQSyOVUBPrnego59PkuORctIo7Jyc7Tv0ggbUSKD9GJw-6y5p-7SAXPftsIQQTIe2yZtWeQfG-UxV984juxhmcXlY_V3v0fw8r8P4BgPrwtYdVZ-shWnB-BVu0S14zqg-R6a0-RKYPkWna6poIvwf-XIwl</recordid><startdate>20160315</startdate><enddate>20160315</enddate><creator>van Loevezijn, Arnold</creator><creator>Venhorst, Jennifer</creator><creator>Iwema Bakker, Wouter I.</creator><creator>Lange, Jos H.M.</creator><creator>de Looff, Wouter</creator><creator>Henzen, Remco</creator><creator>de Vries, Jelle</creator><creator>van de Woestijne, Rob P.</creator><creator>den Hartog, Arnold P.</creator><creator>Verhoog, Stefan</creator><creator>van der Neut, Martina A.W.</creator><creator>de Bruin, Natasja M.W.J.</creator><creator>Kruse, Chris G.</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20160315</creationdate><title>Optimization of N′-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket</title><author>van Loevezijn, Arnold ; Venhorst, Jennifer ; Iwema Bakker, Wouter I. ; Lange, Jos H.M. ; de Looff, Wouter ; Henzen, Remco ; de Vries, Jelle ; van de Woestijne, Rob P. ; den Hartog, Arnold P. ; Verhoog, Stefan ; van der Neut, Martina A.W. ; de Bruin, Natasja M.W.J. ; Kruse, Chris G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-e194t-2ddcf01541086855a8bb976a6848f17d45033ffd36334283dd6fcbf796e126e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>5-HT6 receptor</topic><topic>Binding Sites - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>Molecular modeling</topic><topic>Molecular Structure</topic><topic>Non-basic 5-HT6 antagonists</topic><topic>N′-(Arylsulfonyl)pyrazoline-1-carboxamidines</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Serotonin Antagonists - chemical synthesis</topic><topic>Serotonin Antagonists - chemistry</topic><topic>Serotonin Antagonists - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van Loevezijn, Arnold</creatorcontrib><creatorcontrib>Venhorst, Jennifer</creatorcontrib><creatorcontrib>Iwema Bakker, Wouter I.</creatorcontrib><creatorcontrib>Lange, Jos H.M.</creatorcontrib><creatorcontrib>de Looff, Wouter</creatorcontrib><creatorcontrib>Henzen, Remco</creatorcontrib><creatorcontrib>de Vries, Jelle</creatorcontrib><creatorcontrib>van de Woestijne, Rob P.</creatorcontrib><creatorcontrib>den Hartog, Arnold P.</creatorcontrib><creatorcontrib>Verhoog, Stefan</creatorcontrib><creatorcontrib>van der Neut, Martina A.W.</creatorcontrib><creatorcontrib>de Bruin, Natasja M.W.J.</creatorcontrib><creatorcontrib>Kruse, Chris G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van Loevezijn, Arnold</au><au>Venhorst, Jennifer</au><au>Iwema Bakker, Wouter I.</au><au>Lange, Jos H.M.</au><au>de Looff, Wouter</au><au>Henzen, Remco</au><au>de Vries, Jelle</au><au>van de Woestijne, Rob P.</au><au>den Hartog, Arnold P.</au><au>Verhoog, Stefan</au><au>van der Neut, Martina A.W.</au><au>de Bruin, Natasja M.W.J.</au><au>Kruse, Chris G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimization of N′-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-03-15</date><risdate>2016</risdate><volume>26</volume><issue>6</issue><spage>1605</spage><epage>1611</epage><pages>1605-1611</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The discovery of non-basic N′-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26876931</pmid><doi>10.1016/j.bmcl.2016.02.001</doi><tpages>7</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2016-03, Vol.26 (6), p.1605-1611 |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | 5-HT6 receptor Binding Sites - drug effects Dose-Response Relationship, Drug Humans Molecular Docking Simulation Molecular modeling Molecular Structure Non-basic 5-HT6 antagonists N′-(Arylsulfonyl)pyrazoline-1-carboxamidines Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Receptors, Serotonin - metabolism Serotonin Antagonists - chemical synthesis Serotonin Antagonists - chemistry Serotonin Antagonists - pharmacology Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology |
| title | Optimization of N′-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket |
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