The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate
A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA upt...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 1993-06, Vol.36 (12), p.1716-1725 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1725 |
|---|---|
| container_issue | 12 |
| container_start_page | 1716 |
| container_title | Journal of medicinal chemistry |
| container_volume | 36 |
| creator | Andersen, Knud Erik Braestrup, Claus Groenwald, Frederik C Joergensen, Anker S Nielsen, Erik B Sonnewald, Ursula Soerensen, Per O Suzdak, Peter D Knutsen, Lars J. S |
| description | A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized. |
| doi_str_mv | 10.1021/jm00064a005 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_75768079</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>75768079</sourcerecordid><originalsourceid>FETCH-LOGICAL-a420t-f7e1955fdd2090b9c2ffb1bcc04b1b39d99b8ad44ec47d08a26a782d4d9020f83</originalsourceid><addsrcrecordid>eNptkUuP0zAUhSMEGsrAijWSV0wrcLl2nCZZdoZhQBrxLLBAKHJsp3EnjYsf1eRv8wtwaDVigWTpXvl8PvfKJ0meEpgToOTVZgsAC8YBsnvJhGQUMCuA3U8mAJRiuqDpw-SRc5uIpYSmJ8lJkREgAJPk96pVyA29b5XTDpkG9WavOnS1PF-isPP8RiHdt7rW3lg3R2SOLrsgtORem37k_WjgbRA-WIW58Hqv_RCvgtTKoU5xqfs18uYvKVqjhRrfTT_PMME_2EuGa-2mKd4q3w4dpti3WvVDN8MproMf25-x3emdsjp6KcFtbW6HTgvE4yZoutJ8zeuozBB3iPfxeC1Mvw-diy2SNqyR4L0c11aPkwcN75x6cqynydc3l6uLt_j6w9W7i-U15oyCx02uSJlljZQUSqhLQZumJrUQwGJJS1mWdcElY0qwXELB6YLnBZVMlkChKdLT5PnBd2fNr6Ccr7baCdV1vFcmuCrP8kUBeRnBFwdQWOOcVU21s3rL7VARqMaEq38SjvSzo22ot0rescdIo44PunZe3d7J3N5UizzNs2r18Uv1-vzb9xV7n1efIn924Llw1cYE28dP-e_kP_Dpv6Y</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>75768079</pqid></control><display><type>article</type><title>The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate</title><source>ACS Publications</source><source>MEDLINE</source><creator>Andersen, Knud Erik ; Braestrup, Claus ; Groenwald, Frederik C ; Joergensen, Anker S ; Nielsen, Erik B ; Sonnewald, Ursula ; Soerensen, Per O ; Suzdak, Peter D ; Knutsen, Lars J. S</creator><creatorcontrib>Andersen, Knud Erik ; Braestrup, Claus ; Groenwald, Frederik C ; Joergensen, Anker S ; Nielsen, Erik B ; Sonnewald, Ursula ; Soerensen, Per O ; Suzdak, Peter D ; Knutsen, Lars J. S</creatorcontrib><description>A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00064a005</identifier><identifier>PMID: 8510100</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anticonvulsants - chemical synthesis ; Anticonvulsants - chemistry ; Anticonvulsants - pharmacology ; GABA Antagonists ; gamma-Aminobutyric Acid - metabolism ; Molecular Structure ; Nicotinic Acids - chemistry ; Nipecotic Acids - chemical synthesis ; Nipecotic Acids - chemistry ; Nipecotic Acids - pharmacology ; Proline - analogs & derivatives ; Prosencephalon - metabolism ; Rats ; Stereoisomerism ; Structure-Activity Relationship ; Synaptosomes - drug effects ; Synaptosomes - metabolism ; Tiagabine</subject><ispartof>Journal of medicinal chemistry, 1993-06, Vol.36 (12), p.1716-1725</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a420t-f7e1955fdd2090b9c2ffb1bcc04b1b39d99b8ad44ec47d08a26a782d4d9020f83</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/jm00064a005$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00064a005$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8510100$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Andersen, Knud Erik</creatorcontrib><creatorcontrib>Braestrup, Claus</creatorcontrib><creatorcontrib>Groenwald, Frederik C</creatorcontrib><creatorcontrib>Joergensen, Anker S</creatorcontrib><creatorcontrib>Nielsen, Erik B</creatorcontrib><creatorcontrib>Sonnewald, Ursula</creatorcontrib><creatorcontrib>Soerensen, Per O</creatorcontrib><creatorcontrib>Suzdak, Peter D</creatorcontrib><creatorcontrib>Knutsen, Lars J. S</creatorcontrib><title>The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.</description><subject>Animals</subject><subject>Anticonvulsants - chemical synthesis</subject><subject>Anticonvulsants - chemistry</subject><subject>Anticonvulsants - pharmacology</subject><subject>GABA Antagonists</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Molecular Structure</subject><subject>Nicotinic Acids - chemistry</subject><subject>Nipecotic Acids - chemical synthesis</subject><subject>Nipecotic Acids - chemistry</subject><subject>Nipecotic Acids - pharmacology</subject><subject>Proline - analogs & derivatives</subject><subject>Prosencephalon - metabolism</subject><subject>Rats</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Synaptosomes - drug effects</subject><subject>Synaptosomes - metabolism</subject><subject>Tiagabine</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkUuP0zAUhSMEGsrAijWSV0wrcLl2nCZZdoZhQBrxLLBAKHJsp3EnjYsf1eRv8wtwaDVigWTpXvl8PvfKJ0meEpgToOTVZgsAC8YBsnvJhGQUMCuA3U8mAJRiuqDpw-SRc5uIpYSmJ8lJkREgAJPk96pVyA29b5XTDpkG9WavOnS1PF-isPP8RiHdt7rW3lg3R2SOLrsgtORem37k_WjgbRA-WIW58Hqv_RCvgtTKoU5xqfs18uYvKVqjhRrfTT_PMME_2EuGa-2mKd4q3w4dpti3WvVDN8MproMf25-x3emdsjp6KcFtbW6HTgvE4yZoutJ8zeuozBB3iPfxeC1Mvw-diy2SNqyR4L0c11aPkwcN75x6cqynydc3l6uLt_j6w9W7i-U15oyCx02uSJlljZQUSqhLQZumJrUQwGJJS1mWdcElY0qwXELB6YLnBZVMlkChKdLT5PnBd2fNr6Ccr7baCdV1vFcmuCrP8kUBeRnBFwdQWOOcVU21s3rL7VARqMaEq38SjvSzo22ot0rescdIo44PunZe3d7J3N5UizzNs2r18Uv1-vzb9xV7n1efIn924Llw1cYE28dP-e_kP_Dpv6Y</recordid><startdate>199306</startdate><enddate>199306</enddate><creator>Andersen, Knud Erik</creator><creator>Braestrup, Claus</creator><creator>Groenwald, Frederik C</creator><creator>Joergensen, Anker S</creator><creator>Nielsen, Erik B</creator><creator>Sonnewald, Ursula</creator><creator>Soerensen, Per O</creator><creator>Suzdak, Peter D</creator><creator>Knutsen, Lars J. S</creator><general>American Chemical Society</general><scope>BSCLL</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>199306</creationdate><title>The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate</title><author>Andersen, Knud Erik ; Braestrup, Claus ; Groenwald, Frederik C ; Joergensen, Anker S ; Nielsen, Erik B ; Sonnewald, Ursula ; Soerensen, Per O ; Suzdak, Peter D ; Knutsen, Lars J. S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a420t-f7e1955fdd2090b9c2ffb1bcc04b1b39d99b8ad44ec47d08a26a782d4d9020f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Animals</topic><topic>Anticonvulsants - chemical synthesis</topic><topic>Anticonvulsants - chemistry</topic><topic>Anticonvulsants - pharmacology</topic><topic>GABA Antagonists</topic><topic>gamma-Aminobutyric Acid - metabolism</topic><topic>Molecular Structure</topic><topic>Nicotinic Acids - chemistry</topic><topic>Nipecotic Acids - chemical synthesis</topic><topic>Nipecotic Acids - chemistry</topic><topic>Nipecotic Acids - pharmacology</topic><topic>Proline - analogs & derivatives</topic><topic>Prosencephalon - metabolism</topic><topic>Rats</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Synaptosomes - drug effects</topic><topic>Synaptosomes - metabolism</topic><topic>Tiagabine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Andersen, Knud Erik</creatorcontrib><creatorcontrib>Braestrup, Claus</creatorcontrib><creatorcontrib>Groenwald, Frederik C</creatorcontrib><creatorcontrib>Joergensen, Anker S</creatorcontrib><creatorcontrib>Nielsen, Erik B</creatorcontrib><creatorcontrib>Sonnewald, Ursula</creatorcontrib><creatorcontrib>Soerensen, Per O</creatorcontrib><creatorcontrib>Suzdak, Peter D</creatorcontrib><creatorcontrib>Knutsen, Lars J. S</creatorcontrib><collection>Istex</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>Andersen, Knud Erik</au><au>Braestrup, Claus</au><au>Groenwald, Frederik C</au><au>Joergensen, Anker S</au><au>Nielsen, Erik B</au><au>Sonnewald, Ursula</au><au>Soerensen, Per O</au><au>Suzdak, Peter D</au><au>Knutsen, Lars J. S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1993-06</date><risdate>1993</risdate><volume>36</volume><issue>12</issue><spage>1716</spage><epage>1725</epage><pages>1716-1725</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>8510100</pmid><doi>10.1021/jm00064a005</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1993-06, Vol.36 (12), p.1716-1725 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_75768079 |
| source | ACS Publications; MEDLINE |
| subjects | Animals Anticonvulsants - chemical synthesis Anticonvulsants - chemistry Anticonvulsants - pharmacology GABA Antagonists gamma-Aminobutyric Acid - metabolism Molecular Structure Nicotinic Acids - chemistry Nipecotic Acids - chemical synthesis Nipecotic Acids - chemistry Nipecotic Acids - pharmacology Proline - analogs & derivatives Prosencephalon - metabolism Rats Stereoisomerism Structure-Activity Relationship Synaptosomes - drug effects Synaptosomes - metabolism Tiagabine |
| title | The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (Tiagabine) as an anticonvulsant drug candidate |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T10%3A47%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20synthesis%20of%20novel%20GABA%20uptake%20inhibitors.%201.%20Elucidation%20of%20the%20structure-activity%20studies%20leading%20to%20the%20choice%20of%20(R)-1-%5B4,4-bis(3-methyl-2-thienyl)-3-butenyl%5D-3-piperidinecarboxylic%20acid%20(Tiagabine)%20as%20an%20anticonvulsant%20drug%20candidate&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Andersen,%20Knud%20Erik&rft.date=1993-06&rft.volume=36&rft.issue=12&rft.spage=1716&rft.epage=1725&rft.pages=1716-1725&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm00064a005&rft_dat=%3Cproquest_cross%3E75768079%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=75768079&rft_id=info:pmid/8510100&rfr_iscdi=true |