Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat
In this Letter, we describe the synthesis of constrained diazepanes including 3,9-diazabicyclo[4.2.1]nonane 8a that has improved oral bioavailability and sleep-promoting activity in a rat EEG model. Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists pro...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-07, Vol.20 (14), p.4201-4205 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Coleman, Paul J. Schreier, John D. Roecker, Anthony J. Mercer, Swati P. McGaughey, Georgia B. Cox, Christopher D. Hartman, George D. Harrell, C. Meacham Reiss, Duane R. Doran, Scott M. Garson, Susan L. Anderson, Wayne B. Tang, Cuyue Prueksaritanont, Thomayant Winrow, Christopher J. Renger, John J. |
| description | In this Letter, we describe the synthesis of constrained diazepanes including 3,9-diazabicyclo[4.2.1]nonane 8a that has improved oral bioavailability and sleep-promoting activity in a rat EEG model.
Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model. |
| doi_str_mv | 10.1016/j.bmcl.2010.05.047 |
| format | Article |
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Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.05.047</identifier><identifier>PMID: 20610153</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Alkanes - chemistry ; Alkanes - pharmacokinetics ; Alkanes - pharmacology ; Animals ; Aza Compounds - chemistry ; Aza Compounds - pharmacokinetics ; Aza Compounds - pharmacology ; Biological Availability ; Brain penetration ; Bridged Bicyclo Compounds - chemistry ; Bridged Bicyclo Compounds - pharmacokinetics ; Bridged Bicyclo Compounds - pharmacology ; Diazepane ; Drug Discovery ; Electroencephalography ; GPCR antagonist ; Hypnotics and Sedatives - chemistry ; Hypnotics and Sedatives - pharmacokinetics ; Hypnotics and Sedatives - pharmacology ; Insomnia ; Orexin ; Orexin Receptors ; Rats ; Rats, Sprague-Dawley ; Receptor ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Receptors, Neuropeptide - antagonists & inhibitors ; Sleep</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-07, Vol.20 (14), p.4201-4205</ispartof><rights>2010 Elsevier Ltd</rights><rights>2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-f0b64abcd14900c87c96d943c1167ee1e2aed8edab4182c0c54ddb30ddff4353</citedby><cites>FETCH-LOGICAL-c387t-f0b64abcd14900c87c96d943c1167ee1e2aed8edab4182c0c54ddb30ddff4353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2010.05.047$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3554,27933,27934,46004</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20610153$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coleman, Paul J.</creatorcontrib><creatorcontrib>Schreier, John D.</creatorcontrib><creatorcontrib>Roecker, Anthony J.</creatorcontrib><creatorcontrib>Mercer, Swati P.</creatorcontrib><creatorcontrib>McGaughey, Georgia B.</creatorcontrib><creatorcontrib>Cox, Christopher D.</creatorcontrib><creatorcontrib>Hartman, George D.</creatorcontrib><creatorcontrib>Harrell, C. Meacham</creatorcontrib><creatorcontrib>Reiss, Duane R.</creatorcontrib><creatorcontrib>Doran, Scott M.</creatorcontrib><creatorcontrib>Garson, Susan L.</creatorcontrib><creatorcontrib>Anderson, Wayne B.</creatorcontrib><creatorcontrib>Tang, Cuyue</creatorcontrib><creatorcontrib>Prueksaritanont, Thomayant</creatorcontrib><creatorcontrib>Winrow, Christopher J.</creatorcontrib><creatorcontrib>Renger, John J.</creatorcontrib><title>Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>In this Letter, we describe the synthesis of constrained diazepanes including 3,9-diazabicyclo[4.2.1]nonane 8a that has improved oral bioavailability and sleep-promoting activity in a rat EEG model.
Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.</description><subject>Alkanes - chemistry</subject><subject>Alkanes - pharmacokinetics</subject><subject>Alkanes - pharmacology</subject><subject>Animals</subject><subject>Aza Compounds - chemistry</subject><subject>Aza Compounds - pharmacokinetics</subject><subject>Aza Compounds - pharmacology</subject><subject>Biological Availability</subject><subject>Brain penetration</subject><subject>Bridged Bicyclo Compounds - chemistry</subject><subject>Bridged Bicyclo Compounds - pharmacokinetics</subject><subject>Bridged Bicyclo Compounds - pharmacology</subject><subject>Diazepane</subject><subject>Drug Discovery</subject><subject>Electroencephalography</subject><subject>GPCR antagonist</subject><subject>Hypnotics and Sedatives - chemistry</subject><subject>Hypnotics and Sedatives - pharmacokinetics</subject><subject>Hypnotics and Sedatives - pharmacology</subject><subject>Insomnia</subject><subject>Orexin</subject><subject>Orexin Receptors</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>Receptors, Neuropeptide - antagonists & inhibitors</subject><subject>Sleep</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2LFDEQhoMo7uzqH_AguXmx20on6Q_wIqurwoKXPQgiIZ1U72boTtokMzpe_OtmmNWjngLF876k6iHkGYOaAWtfbetxMXPdQBmArEF0D8iGiVZUXIB8SDYwtFD1g_h8Rs5T2gIwAUI8JmcNtKVB8g359dYlE_YYDzRMlL8cKuv0Tz06czBz-CLqpmZfffDaY6I60TVk9JnanZ5piPjDeRrR4JpDpNpnfRu8SznR7y7f0TQjrtUawxKy87dUm-z2Lh9oSeU7pFHnJ-TRpOeET-_fC3Jz9e7m8kN1_en9x8s315XhfZerCcZW6NFYJgYA03dmaO0guGGs7RAZNhptj1aPgvWNASOFtSMHa6dJcMkvyItTbfnMtx2mrJayN85z2SvskuqkkLwXTf9_kvNWNn3HCtmcSBNDShEntUa36HhQDNRRkNqqoyB1FKRAqiKohJ7f1-_GBe3fyB8jBXh9ArBcY-8wqmQceoPWlUNnZYP7V_9v0j6jzg</recordid><startdate>20100715</startdate><enddate>20100715</enddate><creator>Coleman, Paul J.</creator><creator>Schreier, John D.</creator><creator>Roecker, Anthony J.</creator><creator>Mercer, Swati P.</creator><creator>McGaughey, Georgia B.</creator><creator>Cox, Christopher D.</creator><creator>Hartman, George D.</creator><creator>Harrell, C. Meacham</creator><creator>Reiss, Duane R.</creator><creator>Doran, Scott M.</creator><creator>Garson, Susan L.</creator><creator>Anderson, Wayne B.</creator><creator>Tang, Cuyue</creator><creator>Prueksaritanont, Thomayant</creator><creator>Winrow, Christopher J.</creator><creator>Renger, John J.</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><scope>7QO</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20100715</creationdate><title>Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat</title><author>Coleman, Paul J. ; Schreier, John D. ; Roecker, Anthony J. ; Mercer, Swati P. ; McGaughey, Georgia B. ; Cox, Christopher D. ; Hartman, George D. ; Harrell, C. Meacham ; Reiss, Duane R. ; Doran, Scott M. ; Garson, Susan L. ; Anderson, Wayne B. ; Tang, Cuyue ; Prueksaritanont, Thomayant ; Winrow, Christopher J. ; Renger, John J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-f0b64abcd14900c87c96d943c1167ee1e2aed8edab4182c0c54ddb30ddff4353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Alkanes - chemistry</topic><topic>Alkanes - pharmacokinetics</topic><topic>Alkanes - pharmacology</topic><topic>Animals</topic><topic>Aza Compounds - chemistry</topic><topic>Aza Compounds - pharmacokinetics</topic><topic>Aza Compounds - pharmacology</topic><topic>Biological Availability</topic><topic>Brain penetration</topic><topic>Bridged Bicyclo Compounds - chemistry</topic><topic>Bridged Bicyclo Compounds - pharmacokinetics</topic><topic>Bridged Bicyclo Compounds - pharmacology</topic><topic>Diazepane</topic><topic>Drug Discovery</topic><topic>Electroencephalography</topic><topic>GPCR antagonist</topic><topic>Hypnotics and Sedatives - chemistry</topic><topic>Hypnotics and Sedatives - pharmacokinetics</topic><topic>Hypnotics and Sedatives - pharmacology</topic><topic>Insomnia</topic><topic>Orexin</topic><topic>Orexin Receptors</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor</topic><topic>Receptors, G-Protein-Coupled - antagonists & inhibitors</topic><topic>Receptors, Neuropeptide - antagonists & inhibitors</topic><topic>Sleep</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coleman, Paul J.</creatorcontrib><creatorcontrib>Schreier, John D.</creatorcontrib><creatorcontrib>Roecker, Anthony J.</creatorcontrib><creatorcontrib>Mercer, Swati P.</creatorcontrib><creatorcontrib>McGaughey, Georgia B.</creatorcontrib><creatorcontrib>Cox, Christopher D.</creatorcontrib><creatorcontrib>Hartman, George D.</creatorcontrib><creatorcontrib>Harrell, C. 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Meacham</au><au>Reiss, Duane R.</au><au>Doran, Scott M.</au><au>Garson, Susan L.</au><au>Anderson, Wayne B.</au><au>Tang, Cuyue</au><au>Prueksaritanont, Thomayant</au><au>Winrow, Christopher J.</au><au>Renger, John J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-07-15</date><risdate>2010</risdate><volume>20</volume><issue>14</issue><spage>4201</spage><epage>4205</epage><pages>4201-4205</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>In this Letter, we describe the synthesis of constrained diazepanes including 3,9-diazabicyclo[4.2.1]nonane 8a that has improved oral bioavailability and sleep-promoting activity in a rat EEG model.
Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>20610153</pmid><doi>10.1016/j.bmcl.2010.05.047</doi><tpages>5</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-07, Vol.20 (14), p.4201-4205 |
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| language | eng |
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| subjects | Alkanes - chemistry Alkanes - pharmacokinetics Alkanes - pharmacology Animals Aza Compounds - chemistry Aza Compounds - pharmacokinetics Aza Compounds - pharmacology Biological Availability Brain penetration Bridged Bicyclo Compounds - chemistry Bridged Bicyclo Compounds - pharmacokinetics Bridged Bicyclo Compounds - pharmacology Diazepane Drug Discovery Electroencephalography GPCR antagonist Hypnotics and Sedatives - chemistry Hypnotics and Sedatives - pharmacokinetics Hypnotics and Sedatives - pharmacology Insomnia Orexin Orexin Receptors Rats Rats, Sprague-Dawley Receptor Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, Neuropeptide - antagonists & inhibitors Sleep |
| title | Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat |
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