Bioorganic & medicinal chemistry letters · 2014
Development of novel azabenzofuran TRPA1 antagonists as in vivo tools.
СтатьяНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
Предметные рубрики MeSH
AnimalsCalcium Channel BlockersCalcium ChannelsDisease Models, AnimalDose-Response Relationship, DrugDrug DesignHeterocyclic Compounds, 3-RingHumansIsothiocyanatesMolecular StructureNerve Tissue ProteinsRatsStructure-Activity RelationshipTRPA1 Cation ChannelTRPC Cation ChannelsTransient Receptor Potential Channels