(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT6 Receptor
5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveri...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-07, Vol.53 (14), p.5186-5196 |
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| container_title | Journal of medicinal chemistry |
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| creator | Ivachtchenko, Alexandre V Dmitriev, Dmitri E Golovina, Elena S Kadieva, Madina G Koryakova, Angela G Kysil, Volodymyr M Mitkin, Oleg D Okun, Ilya M Tkachenko, Sergey E Vorobiev, Anton A |
| description | 5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data. |
| doi_str_mv | 10.1021/jm100350r |
| format | Article |
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Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm100350r</identifier><identifier>PMID: 20560595</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amines - chemical synthesis ; Amines - chemistry ; Amines - pharmacology ; Cell Line ; Crystallography, X-Ray ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors ; Humans ; Models, Molecular ; Molecular Structure ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Radioligand Assay ; Receptors, Serotonin - metabolism ; Serotonin 5-HT2 Receptor Antagonists ; Serotonin Antagonists - chemical synthesis ; Serotonin Antagonists - chemistry ; Serotonin Antagonists - pharmacology ; Structure-Activity Relationship ; Sulfones - chemical synthesis ; Sulfones - chemistry ; Sulfones - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2010-07, Vol.53 (14), p.5186-5196</ispartof><rights>Copyright © 2010 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm100350r$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm100350r$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20560595$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ivachtchenko, Alexandre V</creatorcontrib><creatorcontrib>Dmitriev, Dmitri E</creatorcontrib><creatorcontrib>Golovina, Elena S</creatorcontrib><creatorcontrib>Kadieva, Madina G</creatorcontrib><creatorcontrib>Koryakova, Angela G</creatorcontrib><creatorcontrib>Kysil, Volodymyr M</creatorcontrib><creatorcontrib>Mitkin, Oleg D</creatorcontrib><creatorcontrib>Okun, Ilya M</creatorcontrib><creatorcontrib>Tkachenko, Sergey E</creatorcontrib><creatorcontrib>Vorobiev, Anton A</creatorcontrib><title>(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT6 Receptor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.</description><subject>Amines - chemical synthesis</subject><subject>Amines - chemistry</subject><subject>Amines - pharmacology</subject><subject>Cell Line</subject><subject>Crystallography, X-Ray</subject><subject>ERG1 Potassium Channel</subject><subject>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Serotonin 5-HT2 Receptor Antagonists</subject><subject>Serotonin Antagonists - chemical synthesis</subject><subject>Serotonin Antagonists - chemistry</subject><subject>Serotonin Antagonists - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Sulfones - chemical synthesis</subject><subject>Sulfones - chemistry</subject><subject>Sulfones - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kctKxTAQhoMoerwsfAHpRlQwmqRNm7o7iDcQFC8rkZImU-0xTY5NKtRX8KWN19UwM98M88-P0CYlB5QwejjrKCEpJ_0CmlDOCM4EyRbRhBDGMMtZuoJWvZ-RCFGWLqMVRnhOeMkn6GM3xdfPYEfjB9O4GNWojJPmRVr3AIm0OtGP87GX7864B7rPsfxK267VrcUMj2ZPdq0Ff5RcuwA2fI_cggEV2jdIpjbIJ2dbH3zimiQ8Q2z2LsSSTTg-v8uTG1AwD65fR0uNNB42fuMauj89uTs-x5dXZxfH00ssWUYCFoQJXmRAirRpWA6MN0JyrUUULWpaMlYXRZ2KUqgsL2QtGlmWmmsVMQVUp2to52fvvHevA_hQda1XYIy04AZfFZkoC1HSLJJbv-RQd6CredQt-7H6-18Etn8AqXw1c0Nv4-EVJdWXL9W_L-kn-5x-TA</recordid><startdate>20100722</startdate><enddate>20100722</enddate><creator>Ivachtchenko, Alexandre V</creator><creator>Dmitriev, Dmitri E</creator><creator>Golovina, Elena S</creator><creator>Kadieva, Madina G</creator><creator>Koryakova, Angela G</creator><creator>Kysil, Volodymyr M</creator><creator>Mitkin, Oleg D</creator><creator>Okun, Ilya M</creator><creator>Tkachenko, Sergey E</creator><creator>Vorobiev, Anton A</creator><general>American Chemical Society</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>20100722</creationdate><title>(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT6 Receptor</title><author>Ivachtchenko, Alexandre V ; Dmitriev, Dmitri E ; Golovina, Elena S ; Kadieva, Madina G ; Koryakova, Angela G ; Kysil, Volodymyr M ; Mitkin, Oleg D ; Okun, Ilya M ; Tkachenko, Sergey E ; Vorobiev, Anton A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a240t-8028574e073ff26e25f8a5dd88048b1922b77b3898c467ab8fa99d5dcf8ace1d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amines - chemical synthesis</topic><topic>Amines - chemistry</topic><topic>Amines - pharmacology</topic><topic>Cell Line</topic><topic>Crystallography, X-Ray</topic><topic>ERG1 Potassium Channel</topic><topic>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Serotonin 5-HT2 Receptor Antagonists</topic><topic>Serotonin Antagonists - chemical synthesis</topic><topic>Serotonin Antagonists - chemistry</topic><topic>Serotonin Antagonists - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Sulfones - chemical synthesis</topic><topic>Sulfones - chemistry</topic><topic>Sulfones - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ivachtchenko, Alexandre V</creatorcontrib><creatorcontrib>Dmitriev, Dmitri E</creatorcontrib><creatorcontrib>Golovina, Elena S</creatorcontrib><creatorcontrib>Kadieva, Madina G</creatorcontrib><creatorcontrib>Koryakova, Angela G</creatorcontrib><creatorcontrib>Kysil, Volodymyr M</creatorcontrib><creatorcontrib>Mitkin, Oleg D</creatorcontrib><creatorcontrib>Okun, Ilya M</creatorcontrib><creatorcontrib>Tkachenko, Sergey E</creatorcontrib><creatorcontrib>Vorobiev, Anton A</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ivachtchenko, Alexandre V</au><au>Dmitriev, Dmitri E</au><au>Golovina, Elena S</au><au>Kadieva, Madina G</au><au>Koryakova, Angela G</au><au>Kysil, Volodymyr M</au><au>Mitkin, Oleg D</au><au>Okun, Ilya M</au><au>Tkachenko, Sergey E</au><au>Vorobiev, Anton A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT6 Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2010-07-22</date><risdate>2010</risdate><volume>53</volume><issue>14</issue><spage>5186</spage><epage>5196</epage><pages>5186-5196</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>20560595</pmid><doi>10.1021/jm100350r</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2010-07, Vol.53 (14), p.5186-5196 |
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| source | MEDLINE; ACS Publications |
| subjects | Amines - chemical synthesis Amines - chemistry Amines - pharmacology Cell Line Crystallography, X-Ray ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels - antagonists & inhibitors Humans Models, Molecular Molecular Structure Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Radioligand Assay Receptors, Serotonin - metabolism Serotonin 5-HT2 Receptor Antagonists Serotonin Antagonists - chemical synthesis Serotonin Antagonists - chemistry Serotonin Antagonists - pharmacology Structure-Activity Relationship Sulfones - chemical synthesis Sulfones - chemistry Sulfones - pharmacology |
| title | (3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT6 Receptor |
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