N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor
A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R1 moiety and at th...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (17), p.5485-5492 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Vallin, Karl S.A. Sterky, Karin J. Nyman, Eva Bernström, Jenny From, Rebecka Linde, Christian Minidis, Alexander B.E. Nolting, Andreas Närhi, Katja Santangelo, Ellen M. Sehgelmeble, Fernando W. Sohn, Daniel Strindlund, Jennie Weigelt, Dirk |
| description | A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R1 moiety and at the warhead, while the R2 side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca2+-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone. |
| doi_str_mv | 10.1016/j.bmcl.2012.07.032 |
| format | Article |
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Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R1 moiety and at the warhead, while the R2 side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca2+-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.07.032</identifier><identifier>PMID: 22868228</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>amides ; Amides - chemistry ; Amides - pharmacology ; Antagonist ; Antagonists ; Biological and medical sciences ; Calcium - metabolism ; Calcium Channels - metabolism ; carbamates ; Carbamates - chemistry ; Carbamates - pharmacology ; chemistry ; high-throughput screening ; Humans ; Ion channel ; Ion channels ; ketones ; Lead ; Medical sciences ; Nerve Tissue Proteins - antagonists & inhibitors ; Nerve Tissue Proteins - metabolism ; Patch-Clamp Techniques ; Pharmacology. Drug treatments ; screening ; Structure-Activity Relationship ; Transient Receptor Potential Channels - antagonists & inhibitors ; Transient Receptor Potential Channels - metabolism ; transient receptor potential proteins ; TRPA1 ; TRPA1 Cation Channel ; Urea ; Urea - chemistry ; Urea - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-09, Vol.22 (17), p.5485-5492</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-93dbaf710e2aa77b7cdcb58e5de9b0f7f13ee77bf3719e920b796a78cc8dbdd23</citedby><cites>FETCH-LOGICAL-c443t-93dbaf710e2aa77b7cdcb58e5de9b0f7f13ee77bf3719e920b796a78cc8dbdd23</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.2012.07.032$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26340359$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22868228$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vallin, Karl S.A.</creatorcontrib><creatorcontrib>Sterky, Karin J.</creatorcontrib><creatorcontrib>Nyman, Eva</creatorcontrib><creatorcontrib>Bernström, Jenny</creatorcontrib><creatorcontrib>From, Rebecka</creatorcontrib><creatorcontrib>Linde, Christian</creatorcontrib><creatorcontrib>Minidis, Alexander B.E.</creatorcontrib><creatorcontrib>Nolting, Andreas</creatorcontrib><creatorcontrib>Närhi, Katja</creatorcontrib><creatorcontrib>Santangelo, Ellen M.</creatorcontrib><creatorcontrib>Sehgelmeble, Fernando W.</creatorcontrib><creatorcontrib>Sohn, Daniel</creatorcontrib><creatorcontrib>Strindlund, Jennie</creatorcontrib><creatorcontrib>Weigelt, Dirk</creatorcontrib><title>N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R1 moiety and at the warhead, while the R2 side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca2+-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.</description><subject>amides</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>Antagonist</subject><subject>Antagonists</subject><subject>Biological and medical sciences</subject><subject>Calcium - metabolism</subject><subject>Calcium Channels - metabolism</subject><subject>carbamates</subject><subject>Carbamates - chemistry</subject><subject>Carbamates - pharmacology</subject><subject>chemistry</subject><subject>high-throughput screening</subject><subject>Humans</subject><subject>Ion channel</subject><subject>Ion channels</subject><subject>ketones</subject><subject>Lead</subject><subject>Medical sciences</subject><subject>Nerve Tissue Proteins - antagonists & inhibitors</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Patch-Clamp Techniques</subject><subject>Pharmacology. Drug treatments</subject><subject>screening</subject><subject>Structure-Activity Relationship</subject><subject>Transient Receptor Potential Channels - antagonists & inhibitors</subject><subject>Transient Receptor Potential Channels - metabolism</subject><subject>transient receptor potential proteins</subject><subject>TRPA1</subject><subject>TRPA1 Cation Channel</subject><subject>Urea</subject><subject>Urea - chemistry</subject><subject>Urea - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v1DAQhi0EotvCH-AAuSD14tRfiWOJy6pqKVJFEbQSN8uxx8VLEi92tqL_Hke7wA1xGcvWMzPW8yL0ipKaEtqebep-tEPNCGU1kTXh7AlaUdEKzAVpnqIVUS3BnRJfj9BxzhtCqCBCPEdHjHVtV8oKXX3EFK-H748DZjj-jKWa9DhUZgwOcmVyNcUHKPdpNvdxCnnOVfTV_A2q28-f1rRKYGE7x_QCPfNmyPDycJ6gu8uL2_MrfH3z_sP5-hpbIfiMFXe98ZISYMZI2UvrbN900DhQPfHSUw5Q3j2XVIFipJeqNbKztnO9c4yfoNP93G2KP3aQZz2GbGEYzARxlzUlvGspbVr6P6hoCqkWlO1Rm2LOCbzepjAWEwXSi2y90YtsvcjWROoiuzS9Pszf9SO4Py2_7Rbg7QEw2ZrBJzPZkP9ybcmJN6pwb_acN1Gb-1SYuy9lU1MS45SwhXi3J6CofQiQdLYBJgsulABm7WL4109_AVHapGA</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Vallin, Karl S.A.</creator><creator>Sterky, Karin J.</creator><creator>Nyman, Eva</creator><creator>Bernström, Jenny</creator><creator>From, Rebecka</creator><creator>Linde, Christian</creator><creator>Minidis, Alexander B.E.</creator><creator>Nolting, Andreas</creator><creator>Närhi, Katja</creator><creator>Santangelo, Ellen M.</creator><creator>Sehgelmeble, Fernando W.</creator><creator>Sohn, Daniel</creator><creator>Strindlund, Jennie</creator><creator>Weigelt, Dirk</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20120901</creationdate><title>N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor</title><author>Vallin, Karl S.A. ; Sterky, Karin J. ; Nyman, Eva ; Bernström, Jenny ; From, Rebecka ; Linde, Christian ; Minidis, Alexander B.E. ; Nolting, Andreas ; Närhi, Katja ; Santangelo, Ellen M. ; Sehgelmeble, Fernando W. ; Sohn, Daniel ; Strindlund, Jennie ; Weigelt, Dirk</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-93dbaf710e2aa77b7cdcb58e5de9b0f7f13ee77bf3719e920b796a78cc8dbdd23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>amides</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Antagonist</topic><topic>Antagonists</topic><topic>Biological and medical sciences</topic><topic>Calcium - metabolism</topic><topic>Calcium Channels - metabolism</topic><topic>carbamates</topic><topic>Carbamates - chemistry</topic><topic>Carbamates - pharmacology</topic><topic>chemistry</topic><topic>high-throughput screening</topic><topic>Humans</topic><topic>Ion channel</topic><topic>Ion channels</topic><topic>ketones</topic><topic>Lead</topic><topic>Medical sciences</topic><topic>Nerve Tissue Proteins - antagonists & inhibitors</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Patch-Clamp Techniques</topic><topic>Pharmacology. 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Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R1 moiety and at the warhead, while the R2 side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca2+-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22868228</pmid><doi>10.1016/j.bmcl.2012.07.032</doi><tpages>8</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-09, Vol.22 (17), p.5485-5492 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | amides Amides - chemistry Amides - pharmacology Antagonist Antagonists Biological and medical sciences Calcium - metabolism Calcium Channels - metabolism carbamates Carbamates - chemistry Carbamates - pharmacology chemistry high-throughput screening Humans Ion channel Ion channels ketones Lead Medical sciences Nerve Tissue Proteins - antagonists & inhibitors Nerve Tissue Proteins - metabolism Patch-Clamp Techniques Pharmacology. Drug treatments screening Structure-Activity Relationship Transient Receptor Potential Channels - antagonists & inhibitors Transient Receptor Potential Channels - metabolism transient receptor potential proteins TRPA1 TRPA1 Cation Channel Urea Urea - chemistry Urea - pharmacology |
| title | N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor |
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