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
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.05.069