Design, synthesis, and structure–activity relationships of indole-3-heterocycles as agonists of the CB1 receptor
Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-01, Vol.21 (1), p.506-509 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Morrison, Angus J. Adam, Julia M. Baker, James A. Campbell, Robert A. Clark, John K. Cottney, Jean E. Deehan, Maureen Easson, Anna-Marie Fields, Ruth Francis, Stuart Jeremiah, Fiona Keddie, Neil Kiyoi, Takao McArthur, Duncan R. Meyer, Karsten Ratcliffe, Paul D. Schulz, Jurgen Wishart, Grant Yoshiizumi, Kazuya |
| description | Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1. |
| doi_str_mv | 10.1016/j.bmcl.2010.10.093 |
| format | Article |
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This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.10.093</identifier><identifier>PMID: 21075630</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>agonists ; Animals ; Biological and medical sciences ; Cannabinoid ; CB1 receptor ; Drug Design ; GPCR agonist ; Heterocyclic Compounds - chemical synthesis ; Heterocyclic Compounds - chemistry ; Heterocyclic Compounds - pharmacokinetics ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacokinetics ; Medical sciences ; Mice ; Microsomes - metabolism ; Miscellaneous ; Models, Molecular ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; piperazine ; Receptor, Cannabinoid, CB1 - agonists ; Receptor, Cannabinoid, CB1 - metabolism ; Structure-Activity Relationship ; structure-activity relationships ; tail ; Thiadiazoles - chemical synthesis ; Thiadiazoles - chemistry ; Thiadiazoles - pharmacokinetics</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-01, Vol.21 (1), p.506-509</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 Elsevier Ltd. 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This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.</description><subject>agonists</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cannabinoid</subject><subject>CB1 receptor</subject><subject>Drug Design</subject><subject>GPCR agonist</subject><subject>Heterocyclic Compounds - chemical synthesis</subject><subject>Heterocyclic Compounds - chemistry</subject><subject>Heterocyclic Compounds - pharmacokinetics</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacokinetics</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Microsomes - metabolism</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>piperazine</subject><subject>Receptor, Cannabinoid, CB1 - agonists</subject><subject>Receptor, Cannabinoid, CB1 - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><subject>tail</subject><subject>Thiadiazoles - chemical synthesis</subject><subject>Thiadiazoles - chemistry</subject><subject>Thiadiazoles - pharmacokinetics</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1uEzEQxy1ERUPhBTjAXlAv3TD2er8kLhA-WqkSB6jEzXK848TRZp16vJVy6zvwhjwJ3ibArZYlW6Pf_Mf6mbFXHOYcePVuM19uTT8X8FCYQ1s8YTMuK5kXEsqnbAZtBXnTyp-n7DnRBoBLkPIZOxUc6rIqYMbCJyS3Gi4y2g9xne50kemhyyiG0cQx4O_7X9pEd-fiPgvY6-j8QGu3o8zbzA2d7zEv8jVGDN7sTY-U6bRXfnAUH6AUmy0-8tRtcBd9eMFOrO4JXx7PM3bz5fOPxWV-_e3r1eLDdW4ktDHXoNuqFnWNpa3T6rDm1giBbSGs1E3FLV-aCjqol1KDsVgKlNB1jTG6KHVxxs4Pubvgb0ekqLaODPa9HtCPpBrBeduImidSHEgTPFFAq3bBbXXYKw5qUq02alKtJtVTLalOTa-P8eNyi92_lr9uE_D2CGgyurdBD8bRf66oRdWUE_fmwFntlV6FxNx8T5PK9F-FFK1MxPsDgUnXncOgyDgcDHYuSY2q8-6xl_4BonioRA</recordid><startdate>20110101</startdate><enddate>20110101</enddate><creator>Morrison, Angus J.</creator><creator>Adam, Julia M.</creator><creator>Baker, James A.</creator><creator>Campbell, Robert A.</creator><creator>Clark, John K.</creator><creator>Cottney, Jean E.</creator><creator>Deehan, Maureen</creator><creator>Easson, Anna-Marie</creator><creator>Fields, Ruth</creator><creator>Francis, Stuart</creator><creator>Jeremiah, Fiona</creator><creator>Keddie, Neil</creator><creator>Kiyoi, Takao</creator><creator>McArthur, Duncan R.</creator><creator>Meyer, Karsten</creator><creator>Ratcliffe, Paul D.</creator><creator>Schulz, Jurgen</creator><creator>Wishart, Grant</creator><creator>Yoshiizumi, Kazuya</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</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>20110101</creationdate><title>Design, synthesis, and structure–activity relationships of indole-3-heterocycles as agonists of the CB1 receptor</title><author>Morrison, Angus J. ; Adam, Julia M. ; Baker, James A. ; Campbell, Robert A. ; Clark, John K. ; Cottney, Jean E. ; Deehan, Maureen ; Easson, Anna-Marie ; Fields, Ruth ; Francis, Stuart ; Jeremiah, Fiona ; Keddie, Neil ; Kiyoi, Takao ; McArthur, Duncan R. ; Meyer, Karsten ; Ratcliffe, Paul D. ; Schulz, Jurgen ; Wishart, Grant ; Yoshiizumi, Kazuya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-a0a967277e5f7777de71fc22e932f4a861f1bc60d07b4a0cfe52e40dd8cca35a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>agonists</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cannabinoid</topic><topic>CB1 receptor</topic><topic>Drug Design</topic><topic>GPCR agonist</topic><topic>Heterocyclic Compounds - chemical synthesis</topic><topic>Heterocyclic Compounds - chemistry</topic><topic>Heterocyclic Compounds - pharmacokinetics</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacokinetics</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Microsomes - metabolism</topic><topic>Miscellaneous</topic><topic>Models, Molecular</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>piperazine</topic><topic>Receptor, Cannabinoid, CB1 - agonists</topic><topic>Receptor, Cannabinoid, CB1 - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><topic>tail</topic><topic>Thiadiazoles - chemical synthesis</topic><topic>Thiadiazoles - chemistry</topic><topic>Thiadiazoles - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morrison, Angus J.</creatorcontrib><creatorcontrib>Adam, Julia M.</creatorcontrib><creatorcontrib>Baker, James A.</creatorcontrib><creatorcontrib>Campbell, Robert A.</creatorcontrib><creatorcontrib>Clark, John K.</creatorcontrib><creatorcontrib>Cottney, Jean E.</creatorcontrib><creatorcontrib>Deehan, Maureen</creatorcontrib><creatorcontrib>Easson, Anna-Marie</creatorcontrib><creatorcontrib>Fields, Ruth</creatorcontrib><creatorcontrib>Francis, Stuart</creatorcontrib><creatorcontrib>Jeremiah, Fiona</creatorcontrib><creatorcontrib>Keddie, Neil</creatorcontrib><creatorcontrib>Kiyoi, Takao</creatorcontrib><creatorcontrib>McArthur, Duncan R.</creatorcontrib><creatorcontrib>Meyer, Karsten</creatorcontrib><creatorcontrib>Ratcliffe, Paul D.</creatorcontrib><creatorcontrib>Schulz, Jurgen</creatorcontrib><creatorcontrib>Wishart, Grant</creatorcontrib><creatorcontrib>Yoshiizumi, Kazuya</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morrison, Angus J.</au><au>Adam, Julia M.</au><au>Baker, James A.</au><au>Campbell, Robert A.</au><au>Clark, John K.</au><au>Cottney, Jean E.</au><au>Deehan, Maureen</au><au>Easson, Anna-Marie</au><au>Fields, Ruth</au><au>Francis, Stuart</au><au>Jeremiah, Fiona</au><au>Keddie, Neil</au><au>Kiyoi, Takao</au><au>McArthur, Duncan R.</au><au>Meyer, Karsten</au><au>Ratcliffe, Paul D.</au><au>Schulz, Jurgen</au><au>Wishart, Grant</au><au>Yoshiizumi, Kazuya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis, and structure–activity relationships of indole-3-heterocycles as agonists of the CB1 receptor</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-01-01</date><risdate>2011</risdate><volume>21</volume><issue>1</issue><spage>506</spage><epage>509</epage><pages>506-509</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21075630</pmid><doi>10.1016/j.bmcl.2010.10.093</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-01, Vol.21 (1), p.506-509 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | agonists Animals Biological and medical sciences Cannabinoid CB1 receptor Drug Design GPCR agonist Heterocyclic Compounds - chemical synthesis Heterocyclic Compounds - chemistry Heterocyclic Compounds - pharmacokinetics Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacokinetics Medical sciences Mice Microsomes - metabolism Miscellaneous Models, Molecular Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments piperazine Receptor, Cannabinoid, CB1 - agonists Receptor, Cannabinoid, CB1 - metabolism Structure-Activity Relationship structure-activity relationships tail Thiadiazoles - chemical synthesis Thiadiazoles - chemistry Thiadiazoles - pharmacokinetics |
| title | Design, synthesis, and structure–activity relationships of indole-3-heterocycles as agonists of the CB1 receptor |
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