Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators
The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (23), p.6370-6376 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 6376 |
|---|---|
| container_issue | 23 |
| container_start_page | 6370 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 23 |
| creator | Kubas, Holger Meyer, Udo Hechenberger, Mirko Klein, Kai-Uwe Plitt, Patrick Zemribo, Ronalds Spexgoor, Harm W. van Assema, Sander G.A. Abel, Ulrich |
| description | The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development. |
| doi_str_mv | 10.1016/j.bmcl.2013.09.059 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1500757912</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X13011335</els_id><sourcerecordid>1500757912</sourcerecordid><originalsourceid>FETCH-LOGICAL-c413t-e4cbf1a93cf569a6e5dc87e5b3ce2fa747e7c80a2e0fc784f817db13e19778203</originalsourceid><addsrcrecordid>eNqFkcFu1DAQhiMEotvCC3AAH7kkjBM7TiQuVUULUiWESiVu1sSZbL1K4mA7i7jz4DjawhFOc5hvPs3Mn2WvOBQceP3uUHSTGYsSeFVAW4Bsn2Q7LmqRVwLk02wHbQ1504pvZ9l5CAcALkCI59lZKXgpm6beZb_uDA6DG3v24JbFznuGy-IdmgcW3Q_0fWBH9NatgV1ef8lB1gxnHN0-MAxscZHmyCaK2Lno3WIN249rxAkjMU-Glug8k2ymPUZ7JIbj6EIkn8DJ9euIqR9eZM8GHAO9fKwX2f31h69XH_Pbzzefri5vcyN4FXMSphs4tpUZZN1iTbI3jSLZVYbKAZVQpEwDWBIMRjViaLjqO14Rb5VqSqgusrcnb7rw-0oh6skGQ-OIM6ULNZcASqqWl_9HhUjGpoHNWp5Q410Inga9eDuh_6k56C0ofdBbUHoLSkOrU1Bp6PWjf-0m6v-O_EkmAW9OwIBO497boO_vkiGtyKuyFhvx_kRQetnRktfBWJoN9TZ9Pure2X9t8BuaC6_V</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1448208800</pqid></control><display><type>article</type><title>Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Kubas, Holger ; Meyer, Udo ; Hechenberger, Mirko ; Klein, Kai-Uwe ; Plitt, Patrick ; Zemribo, Ronalds ; Spexgoor, Harm W. ; van Assema, Sander G.A. ; Abel, Ulrich</creator><creatorcontrib>Kubas, Holger ; Meyer, Udo ; Hechenberger, Mirko ; Klein, Kai-Uwe ; Plitt, Patrick ; Zemribo, Ronalds ; Spexgoor, Harm W. ; van Assema, Sander G.A. ; Abel, Ulrich</creatorcontrib><description>The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.09.059</identifier><identifier>PMID: 24125886</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>AFQ-056 ; Allosteric modulator ; Allosteric properties ; Allosteric Regulation ; Animals ; CHO Cells ; Cricetulus ; Crystallography, X-Ray ; dyskinesia ; glutamic acid ; Humans ; Indoles - chemistry ; Indoles - pharmacology ; L-dopa ; Metabotropic glutamate receptor ; mGluR5 ; Models, Molecular ; Receptor, Metabotropic Glutamate 5 - chemistry ; Receptor, Metabotropic Glutamate 5 - metabolism ; Scaffold hopping ; solubility ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-12, Vol.23 (23), p.6370-6376</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-e4cbf1a93cf569a6e5dc87e5b3ce2fa747e7c80a2e0fc784f817db13e19778203</citedby><cites>FETCH-LOGICAL-c413t-e4cbf1a93cf569a6e5dc87e5b3ce2fa747e7c80a2e0fc784f817db13e19778203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X13011335$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24125886$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kubas, Holger</creatorcontrib><creatorcontrib>Meyer, Udo</creatorcontrib><creatorcontrib>Hechenberger, Mirko</creatorcontrib><creatorcontrib>Klein, Kai-Uwe</creatorcontrib><creatorcontrib>Plitt, Patrick</creatorcontrib><creatorcontrib>Zemribo, Ronalds</creatorcontrib><creatorcontrib>Spexgoor, Harm W.</creatorcontrib><creatorcontrib>van Assema, Sander G.A.</creatorcontrib><creatorcontrib>Abel, Ulrich</creatorcontrib><title>Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development.</description><subject>AFQ-056</subject><subject>Allosteric modulator</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation</subject><subject>Animals</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Crystallography, X-Ray</subject><subject>dyskinesia</subject><subject>glutamic acid</subject><subject>Humans</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>L-dopa</subject><subject>Metabotropic glutamate receptor</subject><subject>mGluR5</subject><subject>Models, Molecular</subject><subject>Receptor, Metabotropic Glutamate 5 - chemistry</subject><subject>Receptor, Metabotropic Glutamate 5 - metabolism</subject><subject>Scaffold hopping</subject><subject>solubility</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAQhiMEotvCC3AAH7kkjBM7TiQuVUULUiWESiVu1sSZbL1K4mA7i7jz4DjawhFOc5hvPs3Mn2WvOBQceP3uUHSTGYsSeFVAW4Bsn2Q7LmqRVwLk02wHbQ1504pvZ9l5CAcALkCI59lZKXgpm6beZb_uDA6DG3v24JbFznuGy-IdmgcW3Q_0fWBH9NatgV1ef8lB1gxnHN0-MAxscZHmyCaK2Lno3WIN249rxAkjMU-Glug8k2ymPUZ7JIbj6EIkn8DJ9euIqR9eZM8GHAO9fKwX2f31h69XH_Pbzzefri5vcyN4FXMSphs4tpUZZN1iTbI3jSLZVYbKAZVQpEwDWBIMRjViaLjqO14Rb5VqSqgusrcnb7rw-0oh6skGQ-OIM6ULNZcASqqWl_9HhUjGpoHNWp5Q410Inga9eDuh_6k56C0ofdBbUHoLSkOrU1Bp6PWjf-0m6v-O_EkmAW9OwIBO497boO_vkiGtyKuyFhvx_kRQetnRktfBWJoN9TZ9Pure2X9t8BuaC6_V</recordid><startdate>20131201</startdate><enddate>20131201</enddate><creator>Kubas, Holger</creator><creator>Meyer, Udo</creator><creator>Hechenberger, Mirko</creator><creator>Klein, Kai-Uwe</creator><creator>Plitt, Patrick</creator><creator>Zemribo, Ronalds</creator><creator>Spexgoor, Harm W.</creator><creator>van Assema, Sander G.A.</creator><creator>Abel, Ulrich</creator><general>Elsevier Ltd</general><scope>FBQ</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20131201</creationdate><title>Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators</title><author>Kubas, Holger ; Meyer, Udo ; Hechenberger, Mirko ; Klein, Kai-Uwe ; Plitt, Patrick ; Zemribo, Ronalds ; Spexgoor, Harm W. ; van Assema, Sander G.A. ; Abel, Ulrich</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c413t-e4cbf1a93cf569a6e5dc87e5b3ce2fa747e7c80a2e0fc784f817db13e19778203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>AFQ-056</topic><topic>Allosteric modulator</topic><topic>Allosteric properties</topic><topic>Allosteric Regulation</topic><topic>Animals</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Crystallography, X-Ray</topic><topic>dyskinesia</topic><topic>glutamic acid</topic><topic>Humans</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>L-dopa</topic><topic>Metabotropic glutamate receptor</topic><topic>mGluR5</topic><topic>Models, Molecular</topic><topic>Receptor, Metabotropic Glutamate 5 - chemistry</topic><topic>Receptor, Metabotropic Glutamate 5 - metabolism</topic><topic>Scaffold hopping</topic><topic>solubility</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kubas, Holger</creatorcontrib><creatorcontrib>Meyer, Udo</creatorcontrib><creatorcontrib>Hechenberger, Mirko</creatorcontrib><creatorcontrib>Klein, Kai-Uwe</creatorcontrib><creatorcontrib>Plitt, Patrick</creatorcontrib><creatorcontrib>Zemribo, Ronalds</creatorcontrib><creatorcontrib>Spexgoor, Harm W.</creatorcontrib><creatorcontrib>van Assema, Sander G.A.</creatorcontrib><creatorcontrib>Abel, Ulrich</creatorcontrib><collection>AGRIS</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kubas, Holger</au><au>Meyer, Udo</au><au>Hechenberger, Mirko</au><au>Klein, Kai-Uwe</au><au>Plitt, Patrick</au><au>Zemribo, Ronalds</au><au>Spexgoor, Harm W.</au><au>van Assema, Sander G.A.</au><au>Abel, Ulrich</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-12-01</date><risdate>2013</risdate><volume>23</volume><issue>23</issue><spage>6370</spage><epage>6376</epage><pages>6370-6376</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24125886</pmid><doi>10.1016/j.bmcl.2013.09.059</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2013-12, Vol.23 (23), p.6370-6376 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1500757912 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | AFQ-056 Allosteric modulator Allosteric properties Allosteric Regulation Animals CHO Cells Cricetulus Crystallography, X-Ray dyskinesia glutamic acid Humans Indoles - chemistry Indoles - pharmacology L-dopa Metabotropic glutamate receptor mGluR5 Models, Molecular Receptor, Metabotropic Glutamate 5 - chemistry Receptor, Metabotropic Glutamate 5 - metabolism Scaffold hopping solubility Structure-Activity Relationship |
| title | Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T05%3A58%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Scaffold%20hopping%20approach%20towards%20various%20AFQ-056%20analogs%20as%20potent%20metabotropic%20glutamate%20receptor%205%20negative%20allosteric%20modulators&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Kubas,%20Holger&rft.date=2013-12-01&rft.volume=23&rft.issue=23&rft.spage=6370&rft.epage=6376&rft.pages=6370-6376&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2013.09.059&rft_dat=%3Cproquest_cross%3E1500757912%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1448208800&rft_id=info:pmid/24125886&rft_els_id=S0960894X13011335&rfr_iscdi=true |