title: Development of novel azabenzofuran TRPA1 antagonists as in vivo tools.
abstract: 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.
authors: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. Electronic address: kwoodin@amgen.com.
authors: Katrina W
authors: KW
authors: Copeland
authors: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. Electronic address: aboezio@amgen.com.
authors: Alessandro A
authors: AA
authors: Boezio
authors: Department of Pharmaceutics, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Eugene
authors: E
authors: Cheung
authors: Department of Neuroscience, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Josie
authors: J
authors: Lee
authors: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Philip
authors: P
authors: Olivieri
authors: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Laurie B
authors: LB
authors: Schenkel
authors: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Qian
authors: Q
authors: Wan
authors: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors: Weiya
authors: W
authors: Wang
authors: Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Mary C
authors: MC
authors: Wells
authors: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors: Beth
authors: B
authors: Youngblood
authors: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors: Narender R
authors: NR
authors: Gavva
authors: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors: Sonya G
authors: SG
authors: Lehto
authors: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Stephanie
authors: S
authors: Geuns-Meyer
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017879:Isothiocyanates / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D006575:Heterocyclic Compounds, 3-Ring; D017879:Isothiocyanates; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat; C004471:allyl isothiocyanate
keywords: Ion channel; Pain; TRPA1 antagonist