Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists
[Display omitted] A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2014-11, Vol.22 (21), p.6026-6038 |
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| creator | Moritomo, Ayako Yamada, Hiroyoshi Matsuzawa-Nomura, Takaho Watanabe, Toshihiro Itahana, Hirotsune Oku, Makoto Akuzawa, Shinobu Okada, Minoru |
| description | [Display omitted]
A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT2B (Ki=5.1nM) and 5-HT7 (Ki=1.7nM) receptors with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials. |
| doi_str_mv | 10.1016/j.bmc.2014.09.005 |
| format | Article |
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A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT2B (Ki=5.1nM) and 5-HT7 (Ki=1.7nM) receptors with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2014.09.005</identifier><identifier>PMID: 25281269</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>5-HT2B receptor ; 5-HT7 receptor ; Animals ; CHO Cells ; Cricetulus ; Dual antagonist ; Guinea Pigs ; HEK293 Cells ; Humans ; Migraine ; Molecular Docking Simulation ; Optical resolution ; Receptor, Serotonin, 5-HT2B - metabolism ; Receptors, Serotonin - metabolism ; Serotonin 5-HT2 Receptor Antagonists - chemical synthesis ; Serotonin 5-HT2 Receptor Antagonists - chemistry ; Serotonin 5-HT2 Receptor Antagonists - pharmacology ; Serotonin Antagonists - chemical synthesis ; Serotonin Antagonists - chemistry ; Serotonin Antagonists - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry, 2014-11, Vol.22 (21), p.6026-6038</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c419t-8c59e521f5574c63e207cafc7880ebd06387cc0a8d64768002d5f1caf2b553da3</citedby><cites>FETCH-LOGICAL-c419t-8c59e521f5574c63e207cafc7880ebd06387cc0a8d64768002d5f1caf2b553da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2014.09.005$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25281269$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Yamada, Hiroyoshi</creatorcontrib><creatorcontrib>Matsuzawa-Nomura, Takaho</creatorcontrib><creatorcontrib>Watanabe, Toshihiro</creatorcontrib><creatorcontrib>Itahana, Hirotsune</creatorcontrib><creatorcontrib>Oku, Makoto</creatorcontrib><creatorcontrib>Akuzawa, Shinobu</creatorcontrib><creatorcontrib>Okada, Minoru</creatorcontrib><title>Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT2B (Ki=5.1nM) and 5-HT7 (Ki=1.7nM) receptors with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.</description><subject>5-HT2B receptor</subject><subject>5-HT7 receptor</subject><subject>Animals</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Dual antagonist</subject><subject>Guinea Pigs</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Migraine</subject><subject>Molecular Docking Simulation</subject><subject>Optical resolution</subject><subject>Receptor, Serotonin, 5-HT2B - metabolism</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Serotonin 5-HT2 Receptor Antagonists - chemical synthesis</subject><subject>Serotonin 5-HT2 Receptor Antagonists - chemistry</subject><subject>Serotonin 5-HT2 Receptor Antagonists - pharmacology</subject><subject>Serotonin Antagonists - chemical synthesis</subject><subject>Serotonin Antagonists - chemistry</subject><subject>Serotonin Antagonists - pharmacology</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EotvCA3BBPnIgwXZiJxYnWlGKVIkD5Ww59mTrlWMHO4m0L8Ez42ULR04zGn3_P5r5EXpDSU0JFR8O9TCZmhHa1kTWhPBnaEdb0VZNI-lztCNS9BXppbhAlzkfCCGslfQlumCc9ZQJuUO_vh_D8gjZZayDxfOjTpM20ce9M9pj2LRf9eJiwHHEcV5OU3_E85rgPQ5xA4-NTkMMR4_3qw7OugDYQnJbkW1QbDO2a7Hi1d0Du_6z5dR2OIGBeYmpjBa9j8HlJb9CL0btM7x-qlfox-3nh5u76v7bl683n-4r01K5VL3hEjijI-dda0QDjHRGj6brewKDJaLpO2OI7q1oO9GXuy0faSHYwHljdXOF3p195xR_rpAXNblswHsdIK5ZUcGk5Jw0bUHpGTUp5pxgVHNyk05HRYk6xaAOqsSgTjEoIlWJoWjePtmvwwT2n-Lv3wvw8QxAOXJzkFQ2DoIB68pbFmWj-4_9b07ameE</recordid><startdate>20141101</startdate><enddate>20141101</enddate><creator>Moritomo, Ayako</creator><creator>Yamada, Hiroyoshi</creator><creator>Matsuzawa-Nomura, Takaho</creator><creator>Watanabe, Toshihiro</creator><creator>Itahana, Hirotsune</creator><creator>Oku, Makoto</creator><creator>Akuzawa, Shinobu</creator><creator>Okada, Minoru</creator><general>Elsevier Ltd</general><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>20141101</creationdate><title>Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists</title><author>Moritomo, Ayako ; Yamada, Hiroyoshi ; Matsuzawa-Nomura, Takaho ; Watanabe, Toshihiro ; Itahana, Hirotsune ; Oku, Makoto ; Akuzawa, Shinobu ; Okada, Minoru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c419t-8c59e521f5574c63e207cafc7880ebd06387cc0a8d64768002d5f1caf2b553da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>5-HT2B receptor</topic><topic>5-HT7 receptor</topic><topic>Animals</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Dual antagonist</topic><topic>Guinea Pigs</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Migraine</topic><topic>Molecular Docking Simulation</topic><topic>Optical resolution</topic><topic>Receptor, Serotonin, 5-HT2B - metabolism</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Serotonin 5-HT2 Receptor Antagonists - chemical synthesis</topic><topic>Serotonin 5-HT2 Receptor Antagonists - chemistry</topic><topic>Serotonin 5-HT2 Receptor Antagonists - pharmacology</topic><topic>Serotonin Antagonists - chemical synthesis</topic><topic>Serotonin Antagonists - chemistry</topic><topic>Serotonin Antagonists - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Yamada, Hiroyoshi</creatorcontrib><creatorcontrib>Matsuzawa-Nomura, Takaho</creatorcontrib><creatorcontrib>Watanabe, Toshihiro</creatorcontrib><creatorcontrib>Itahana, Hirotsune</creatorcontrib><creatorcontrib>Oku, Makoto</creatorcontrib><creatorcontrib>Akuzawa, Shinobu</creatorcontrib><creatorcontrib>Okada, Minoru</creatorcontrib><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</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moritomo, Ayako</au><au>Yamada, Hiroyoshi</au><au>Matsuzawa-Nomura, Takaho</au><au>Watanabe, Toshihiro</au><au>Itahana, Hirotsune</au><au>Oku, Makoto</au><au>Akuzawa, Shinobu</au><au>Okada, Minoru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2014-11-01</date><risdate>2014</risdate><volume>22</volume><issue>21</issue><spage>6026</spage><epage>6038</epage><pages>6026-6038</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT2B (Ki=5.1nM) and 5-HT7 (Ki=1.7nM) receptors with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25281269</pmid><doi>10.1016/j.bmc.2014.09.005</doi><tpages>13</tpages></addata></record> |
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| subjects | 5-HT2B receptor 5-HT7 receptor Animals CHO Cells Cricetulus Dual antagonist Guinea Pigs HEK293 Cells Humans Migraine Molecular Docking Simulation Optical resolution Receptor, Serotonin, 5-HT2B - metabolism Receptors, Serotonin - metabolism Serotonin 5-HT2 Receptor Antagonists - chemical synthesis Serotonin 5-HT2 Receptor Antagonists - chemistry Serotonin 5-HT2 Receptor Antagonists - pharmacology Serotonin Antagonists - chemical synthesis Serotonin Antagonists - chemistry Serotonin Antagonists - pharmacology |
| title | Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists |
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