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Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators
[Display omitted] This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure–activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activi...
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| Published in: | Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (16), p.3135-3141 |
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| Main Authors: | , , , , , , , , , |
| Format: | Article |
| Language: | English |
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| container_end_page | 3141 |
| container_issue | 16 |
| container_start_page | 3135 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 25 |
| creator | Yoshikawa, Keita Ohyama, Tomofumi Takahashi, Eiki Numajiri, Yoshitaka Konno, Mitsuhiro Moriyama, Masaki Takemi, Natsumi Kunita, Kana Nishimura, Kazumi Hayashi, Ryoji |
| description | [Display omitted]
This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure–activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia. |
| doi_str_mv | 10.1016/j.bmcl.2015.06.008 |
| format | article |
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This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure–activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.06.008</identifier><identifier>PMID: 26112438</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acylamines ; Administration, Oral ; Allosteric Regulation ; Amines - chemical synthesis ; Amines - chemistry ; Amines - pharmacology ; Animals ; Anti-Anxiety Agents - chemical synthesis ; Anti-Anxiety Agents - chemistry ; Anti-Anxiety Agents - pharmacology ; Crystallography, X-Ray ; Disease Models, Animal ; Hyperthermia, Induced ; Metabotropic glutamate receptor ; mGluR5 negative allosteric modulators ; Mice ; Molecular Conformation ; Receptor, Metabotropic Glutamate 5 - chemistry ; Receptor, Metabotropic Glutamate 5 - metabolism ; Rectum - drug effects ; Rectum - physiology ; Stereoisomerism ; Structure-Activity Relationship ; Temperature</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-08, Vol.25 (16), p.3135-3141</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c377t-3db56ee61302549c7f2285130a1d835f8888dc029304a62ba02857dacc482a403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26112438$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoshikawa, Keita</creatorcontrib><creatorcontrib>Ohyama, Tomofumi</creatorcontrib><creatorcontrib>Takahashi, Eiki</creatorcontrib><creatorcontrib>Numajiri, Yoshitaka</creatorcontrib><creatorcontrib>Konno, Mitsuhiro</creatorcontrib><creatorcontrib>Moriyama, Masaki</creatorcontrib><creatorcontrib>Takemi, Natsumi</creatorcontrib><creatorcontrib>Kunita, Kana</creatorcontrib><creatorcontrib>Nishimura, Kazumi</creatorcontrib><creatorcontrib>Hayashi, Ryoji</creatorcontrib><title>Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure–activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.</description><subject>Acylamines</subject><subject>Administration, Oral</subject><subject>Allosteric Regulation</subject><subject>Amines - chemical synthesis</subject><subject>Amines - chemistry</subject><subject>Amines - pharmacology</subject><subject>Animals</subject><subject>Anti-Anxiety Agents - chemical synthesis</subject><subject>Anti-Anxiety Agents - chemistry</subject><subject>Anti-Anxiety Agents - pharmacology</subject><subject>Crystallography, X-Ray</subject><subject>Disease Models, Animal</subject><subject>Hyperthermia, Induced</subject><subject>Metabotropic glutamate receptor</subject><subject>mGluR5 negative allosteric modulators</subject><subject>Mice</subject><subject>Molecular Conformation</subject><subject>Receptor, Metabotropic Glutamate 5 - chemistry</subject><subject>Receptor, Metabotropic Glutamate 5 - metabolism</subject><subject>Rectum - drug effects</subject><subject>Rectum - physiology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Temperature</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNp9kE2LFDEQhoMo7uzqH_AgOXrYbivpdLobvMjifsCCILvgLaSTas2Q7oxJenD-vZmd1aO5hKKe94V6CHnHoGbA5MdtPc7G1xxYW4OsAfoXZMOEFFUjoH1JNjBIqPpBfD8j5yltAZgAIV6TMy4Z46LpN-T3ncUlu8kZnV1YaJio9rufukrrmLLLa0ZLtTl4PbsFE9WJLmGP_pLuQi7JS6oXS0PU3h8Kl90e6Xzj128tXfCHfprLLqSM0Rk6B7t6nUNMb8irSfuEb5__C_J4_eXh6ra6_3pzd_X5vjJN1-WqsWMrESVrgLdiMN3Eed-WSTPbN-3Ul2cN8KEBoSUfNZR1Z7UxoudaQHNBPpx6dzH8WjFlNbtk0Hu9YFiTYnIQHUgJoqD8hJoYUoo4qV10s44HxUAdjautOhpXR-MKpCrGS-j9c_86zmj_Rf4qLsCnE4Dlyr3DqJJxuBi0LqLJygb3v_4_-jCTKQ</recordid><startdate>20150815</startdate><enddate>20150815</enddate><creator>Yoshikawa, Keita</creator><creator>Ohyama, Tomofumi</creator><creator>Takahashi, Eiki</creator><creator>Numajiri, Yoshitaka</creator><creator>Konno, Mitsuhiro</creator><creator>Moriyama, Masaki</creator><creator>Takemi, Natsumi</creator><creator>Kunita, Kana</creator><creator>Nishimura, Kazumi</creator><creator>Hayashi, Ryoji</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>20150815</creationdate><title>Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators</title><author>Yoshikawa, Keita ; Ohyama, Tomofumi ; Takahashi, Eiki ; Numajiri, Yoshitaka ; Konno, Mitsuhiro ; Moriyama, Masaki ; Takemi, Natsumi ; Kunita, Kana ; Nishimura, Kazumi ; Hayashi, Ryoji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c377t-3db56ee61302549c7f2285130a1d835f8888dc029304a62ba02857dacc482a403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acylamines</topic><topic>Administration, Oral</topic><topic>Allosteric Regulation</topic><topic>Amines - chemical synthesis</topic><topic>Amines - chemistry</topic><topic>Amines - pharmacology</topic><topic>Animals</topic><topic>Anti-Anxiety Agents - chemical synthesis</topic><topic>Anti-Anxiety Agents - chemistry</topic><topic>Anti-Anxiety Agents - pharmacology</topic><topic>Crystallography, X-Ray</topic><topic>Disease Models, Animal</topic><topic>Hyperthermia, Induced</topic><topic>Metabotropic glutamate receptor</topic><topic>mGluR5 negative allosteric modulators</topic><topic>Mice</topic><topic>Molecular Conformation</topic><topic>Receptor, Metabotropic Glutamate 5 - chemistry</topic><topic>Receptor, Metabotropic Glutamate 5 - metabolism</topic><topic>Rectum - drug effects</topic><topic>Rectum - physiology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Temperature</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yoshikawa, Keita</creatorcontrib><creatorcontrib>Ohyama, Tomofumi</creatorcontrib><creatorcontrib>Takahashi, Eiki</creatorcontrib><creatorcontrib>Numajiri, Yoshitaka</creatorcontrib><creatorcontrib>Konno, Mitsuhiro</creatorcontrib><creatorcontrib>Moriyama, Masaki</creatorcontrib><creatorcontrib>Takemi, Natsumi</creatorcontrib><creatorcontrib>Kunita, Kana</creatorcontrib><creatorcontrib>Nishimura, Kazumi</creatorcontrib><creatorcontrib>Hayashi, Ryoji</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 letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yoshikawa, Keita</au><au>Ohyama, Tomofumi</au><au>Takahashi, Eiki</au><au>Numajiri, Yoshitaka</au><au>Konno, Mitsuhiro</au><au>Moriyama, Masaki</au><au>Takemi, Natsumi</au><au>Kunita, Kana</au><au>Nishimura, Kazumi</au><au>Hayashi, Ryoji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-08-15</date><risdate>2015</risdate><volume>25</volume><issue>16</issue><spage>3135</spage><epage>3141</epage><pages>3135-3141</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure–activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26112438</pmid><doi>10.1016/j.bmcl.2015.06.008</doi><tpages>7</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2015-08, Vol.25 (16), p.3135-3141 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | Elsevier |
| subjects | Acylamines Administration, Oral Allosteric Regulation Amines - chemical synthesis Amines - chemistry Amines - pharmacology Animals Anti-Anxiety Agents - chemical synthesis Anti-Anxiety Agents - chemistry Anti-Anxiety Agents - pharmacology Crystallography, X-Ray Disease Models, Animal Hyperthermia, Induced Metabotropic glutamate receptor mGluR5 negative allosteric modulators Mice Molecular Conformation Receptor, Metabotropic Glutamate 5 - chemistry Receptor, Metabotropic Glutamate 5 - metabolism Rectum - drug effects Rectum - physiology Stereoisomerism Structure-Activity Relationship Temperature |
| title | Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators |
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