Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the α2-δ Protein
As part of a program aimed at generating compounds with affinity for the α2-δ subunit of voltage-gated calcium channels, several novel β-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids co...
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| Veröffentlicht in: | Journal of medicinal chemistry 2005-04, Vol.48 (8), p.3026-3035 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 48 |
| creator | Schwarz, Jacob B Gibbons, Sian E Graham, Shelley R Colbry, Norman L Guzzo, Peter R Le, Van-Duc Vartanian, Mark G Kinsora, Jack J Lotarski, Susan M Li, Zheng Dickerson, Melvin R Su, Ti-Zhi Weber, Mark L El-Kattan, Ayman Thorpe, Andrew J Donevan, Sean D Taylor, Charles P Wustrow, David J |
| description | As part of a program aimed at generating compounds with affinity for the α2-δ subunit of voltage-gated calcium channels, several novel β-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the α2-δ subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood−brain barrier. |
| doi_str_mv | 10.1021/jm0491086 |
| format | Article |
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Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the α2-δ subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood−brain barrier.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0491086</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Anticonvulsants. Antiepileptics. Antiparkinson agents ; Biological and medical sciences ; Medical sciences ; Neuropharmacology ; Pharmacology. Drug treatments</subject><ispartof>Journal of medicinal chemistry, 2005-04, Vol.48 (8), p.3026-3035</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2005 INIST-CNRS</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/jm0491086$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0491086$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,778,782,27059,27907,27908,56721,56771</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16740262$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>Schwarz, Jacob B</creatorcontrib><creatorcontrib>Gibbons, Sian E</creatorcontrib><creatorcontrib>Graham, Shelley R</creatorcontrib><creatorcontrib>Colbry, Norman L</creatorcontrib><creatorcontrib>Guzzo, Peter R</creatorcontrib><creatorcontrib>Le, Van-Duc</creatorcontrib><creatorcontrib>Vartanian, Mark G</creatorcontrib><creatorcontrib>Kinsora, Jack J</creatorcontrib><creatorcontrib>Lotarski, Susan M</creatorcontrib><creatorcontrib>Li, Zheng</creatorcontrib><creatorcontrib>Dickerson, Melvin R</creatorcontrib><creatorcontrib>Su, Ti-Zhi</creatorcontrib><creatorcontrib>Weber, Mark L</creatorcontrib><creatorcontrib>El-Kattan, Ayman</creatorcontrib><creatorcontrib>Thorpe, Andrew J</creatorcontrib><creatorcontrib>Donevan, Sean D</creatorcontrib><creatorcontrib>Taylor, Charles P</creatorcontrib><creatorcontrib>Wustrow, David J</creatorcontrib><title>Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the α2-δ Protein</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>As part of a program aimed at generating compounds with affinity for the α2-δ subunit of voltage-gated calcium channels, several novel β-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the α2-δ subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood−brain barrier.</description><subject>Anticonvulsants. Antiepileptics. Antiparkinson agents</subject><subject>Biological and medical sciences</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNpFkM9OwzAMxiMEEmNw4A1y4Rhw_jRpj93EBtIEkygXLlGapltH11ZNh9hjgXiOPROdhoZ8sK3P_mT_ELqmcEuB0bvVGkREIZQnaEADBkSEIE7RAIAxwiTj5-jC-xUAcMr4ALmn-sOVeLy1Zd20dbMt8e6bxOuiqnFsiwzHlSnrxcZ5XOd43rqFSU1ZVNhUGZ72deOqrm-TpelwYtqF63C3dHj3xcjup1-oO1dUl-gsN6V3V395iF4n98n4gcyep4_jeEYMlWFHVATgHA9EJPuzc8gENZE1eWpdH0qEmcrCUPWPOiFTsDJIucwC0YuCR3nIh-jm4NsYb02Zt6ayhddNW6xNu9VUKgF7CENEDnOF79znUTftu5aKq0An8xc9moxmis3fdPDva6zXq3rT9lC8pqD3zPWROf8FEQh0Mg</recordid><startdate>20050421</startdate><enddate>20050421</enddate><creator>Schwarz, Jacob B</creator><creator>Gibbons, Sian E</creator><creator>Graham, Shelley R</creator><creator>Colbry, Norman L</creator><creator>Guzzo, Peter R</creator><creator>Le, Van-Duc</creator><creator>Vartanian, Mark G</creator><creator>Kinsora, Jack J</creator><creator>Lotarski, Susan M</creator><creator>Li, Zheng</creator><creator>Dickerson, Melvin R</creator><creator>Su, Ti-Zhi</creator><creator>Weber, Mark L</creator><creator>El-Kattan, Ayman</creator><creator>Thorpe, Andrew J</creator><creator>Donevan, Sean D</creator><creator>Taylor, Charles P</creator><creator>Wustrow, David J</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope></search><sort><creationdate>20050421</creationdate><title>Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the α2-δ Protein</title><author>Schwarz, Jacob B ; Gibbons, Sian E ; Graham, Shelley R ; Colbry, Norman L ; Guzzo, Peter R ; Le, Van-Duc ; Vartanian, Mark G ; Kinsora, Jack J ; Lotarski, Susan M ; Li, Zheng ; Dickerson, Melvin R ; Su, Ti-Zhi ; Weber, Mark L ; El-Kattan, Ayman ; Thorpe, Andrew J ; Donevan, Sean D ; Taylor, Charles P ; Wustrow, David J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a168t-7900ee35496480f0d41a9cafbcecec748d7d887102e46b0c65b36d54cec439f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Anticonvulsants. Antiepileptics. Antiparkinson agents</topic><topic>Biological and medical sciences</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schwarz, Jacob B</creatorcontrib><creatorcontrib>Gibbons, Sian E</creatorcontrib><creatorcontrib>Graham, Shelley R</creatorcontrib><creatorcontrib>Colbry, Norman L</creatorcontrib><creatorcontrib>Guzzo, Peter R</creatorcontrib><creatorcontrib>Le, Van-Duc</creatorcontrib><creatorcontrib>Vartanian, Mark G</creatorcontrib><creatorcontrib>Kinsora, Jack J</creatorcontrib><creatorcontrib>Lotarski, Susan M</creatorcontrib><creatorcontrib>Li, Zheng</creatorcontrib><creatorcontrib>Dickerson, Melvin R</creatorcontrib><creatorcontrib>Su, Ti-Zhi</creatorcontrib><creatorcontrib>Weber, Mark L</creatorcontrib><creatorcontrib>El-Kattan, Ayman</creatorcontrib><creatorcontrib>Thorpe, Andrew J</creatorcontrib><creatorcontrib>Donevan, Sean D</creatorcontrib><creatorcontrib>Taylor, Charles P</creatorcontrib><creatorcontrib>Wustrow, David J</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schwarz, Jacob B</au><au>Gibbons, Sian E</au><au>Graham, Shelley R</au><au>Colbry, Norman L</au><au>Guzzo, Peter R</au><au>Le, Van-Duc</au><au>Vartanian, Mark G</au><au>Kinsora, Jack J</au><au>Lotarski, Susan M</au><au>Li, Zheng</au><au>Dickerson, Melvin R</au><au>Su, Ti-Zhi</au><au>Weber, Mark L</au><au>El-Kattan, Ayman</au><au>Thorpe, Andrew J</au><au>Donevan, Sean D</au><au>Taylor, Charles P</au><au>Wustrow, David J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the α2-δ Protein</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2005-04-21</date><risdate>2005</risdate><volume>48</volume><issue>8</issue><spage>3026</spage><epage>3035</epage><pages>3026-3035</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>As part of a program aimed at generating compounds with affinity for the α2-δ subunit of voltage-gated calcium channels, several novel β-amino acids were prepared using an efficient nitroalkane-mediated cyclopropanation as a key step. Depending on the ester that was chosen, the target amino acids could be prepared in as few as three steps. The cyclopropyl amino acids derived from ketones proved to be potent binders of the α2-δ subunit of voltage-gated calcium channels, but did not interact with the large neutral amino acid system L (leucine) transporter. Anticonvulsant effects were observed in vivo with compound 34 but only after intracerebroventricular (icv) administration, presumably due to inadequate brain concentrations of the drug being achieved following oral dosing. However, pregabalin 1 was active in the DBA/2 model after oral (and icv) dosing, supporting a hypothesis that active transport is a prerequisite for such zwitterionic species to cross the blood−brain barrier.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><doi>10.1021/jm0491086</doi><tpages>10</tpages></addata></record> |
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| source | ACS Publications |
| subjects | Anticonvulsants. Antiepileptics. Antiparkinson agents Biological and medical sciences Medical sciences Neuropharmacology Pharmacology. Drug treatments |
| title | Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the α2-δ Protein |
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