Development of novel azabenzofuran TRPA1 antagonists as in vivo tools
The transient receptor potential ankyrin 1 (TRPA1) channel is activated by noxious stimuli including chemical irritants and endogenous inflammatory mediators. Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A n...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (15), p.3464-3468 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Copeland, Katrina W Boezio, Alessandro A Cheung, Eugene Lee, Josie Olivieri, Philip Schenkel, Laurie B Wan, Qian Wang, Weiya Wells, Mary C Youngblood, Beth Gavva, Narender R Lehto, Sonya G Geuns-Meyer, Stephanie |
| description | The transient receptor potential ankyrin 1 (TRPA1) channel is activated by noxious stimuli including chemical irritants and endogenous inflammatory mediators. Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A novel azabenzofuran series was developed that demonstrated in vitro inhibition of allyl isothiocyanate (AITC)-induced (45)Ca(2+) uptake with nanomolar potencies against both human and rat TRPA1. From this series, compound 10 demonstrated in vivo target coverage in an AITC-induced flinching model in rats while providing unbound plasma concentrations up to 16-fold higher than the TRPA1 rat IC50. |
| doi_str_mv | 10.1016/j.bmcl.2014.05.069 |
| format | Article |
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Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A novel azabenzofuran series was developed that demonstrated in vitro inhibition of allyl isothiocyanate (AITC)-induced (45)Ca(2+) uptake with nanomolar potencies against both human and rat TRPA1. From this series, compound 10 demonstrated in vivo target coverage in an AITC-induced flinching model in rats while providing unbound plasma concentrations up to 16-fold higher than the TRPA1 rat IC50.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.05.069</identifier><identifier>PMID: 24953819</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Calcium Channel Blockers - chemical synthesis ; Calcium Channel Blockers - chemistry ; Calcium Channel Blockers - pharmacology ; Calcium Channels - metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Design ; Heterocyclic Compounds, 3-Ring - chemical synthesis ; Heterocyclic Compounds, 3-Ring - chemistry ; Heterocyclic Compounds, 3-Ring - pharmacology ; Humans ; Isothiocyanates - antagonists & inhibitors ; Molecular Structure ; Nerve Tissue Proteins - antagonists & inhibitors ; Nerve Tissue Proteins - metabolism ; Rats ; Structure-Activity Relationship ; Transient Receptor Potential Channels - antagonists & inhibitors ; Transient Receptor Potential Channels - metabolism ; TRPA1 Cation Channel ; TRPC Cation Channels - antagonists & inhibitors ; TRPC Cation Channels - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-08, Vol.24 (15), p.3464-3468</ispartof><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-456933fa1abc1e2d7f58e0ae3020e76c23e8a3970b90d182520ab1f5268fc03f3</citedby><cites>FETCH-LOGICAL-c406t-456933fa1abc1e2d7f58e0ae3020e76c23e8a3970b90d182520ab1f5268fc03f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24953819$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Copeland, Katrina W</creatorcontrib><creatorcontrib>Boezio, Alessandro A</creatorcontrib><creatorcontrib>Cheung, Eugene</creatorcontrib><creatorcontrib>Lee, Josie</creatorcontrib><creatorcontrib>Olivieri, Philip</creatorcontrib><creatorcontrib>Schenkel, Laurie B</creatorcontrib><creatorcontrib>Wan, Qian</creatorcontrib><creatorcontrib>Wang, Weiya</creatorcontrib><creatorcontrib>Wells, Mary C</creatorcontrib><creatorcontrib>Youngblood, Beth</creatorcontrib><creatorcontrib>Gavva, Narender R</creatorcontrib><creatorcontrib>Lehto, Sonya G</creatorcontrib><creatorcontrib>Geuns-Meyer, Stephanie</creatorcontrib><title>Development of novel azabenzofuran TRPA1 antagonists as in vivo tools</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The transient receptor potential ankyrin 1 (TRPA1) channel is activated by noxious stimuli including chemical irritants and endogenous inflammatory mediators. Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A novel azabenzofuran series was developed that demonstrated in vitro inhibition of allyl isothiocyanate (AITC)-induced (45)Ca(2+) uptake with nanomolar potencies against both human and rat TRPA1. 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Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A novel azabenzofuran series was developed that demonstrated in vitro inhibition of allyl isothiocyanate (AITC)-induced (45)Ca(2+) uptake with nanomolar potencies against both human and rat TRPA1. From this series, compound 10 demonstrated in vivo target coverage in an AITC-induced flinching model in rats while providing unbound plasma concentrations up to 16-fold higher than the TRPA1 rat IC50.</abstract><cop>England</cop><pmid>24953819</pmid><doi>10.1016/j.bmcl.2014.05.069</doi><tpages>5</tpages></addata></record> |
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| subjects | Animals Calcium Channel Blockers - chemical synthesis Calcium Channel Blockers - chemistry Calcium Channel Blockers - pharmacology Calcium Channels - metabolism Disease Models, Animal Dose-Response Relationship, Drug Drug Design Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Humans Isothiocyanates - antagonists & inhibitors Molecular Structure Nerve Tissue Proteins - antagonists & inhibitors Nerve Tissue Proteins - metabolism Rats Structure-Activity Relationship Transient Receptor Potential Channels - antagonists & inhibitors Transient Receptor Potential Channels - metabolism TRPA1 Cation Channel TRPC Cation Channels - antagonists & inhibitors TRPC Cation Channels - metabolism |
| title | Development of novel azabenzofuran TRPA1 antagonists as in vivo tools |
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