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Development of novel azabenzofuran TRPA1 antagonists as in vivo tools.
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.
Afiliação
  • Copeland KW; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. Electronic address: kwoodin@amgen.com.
  • Boezio AA; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. Electronic address: aboezio@amgen.com.
  • Cheung E; Department of Pharmaceutics, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • Lee J; Department of Neuroscience, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • Olivieri P; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • Schenkel LB; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • Wan Q; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • Wang W; Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
  • Wells MC; Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • Youngblood B; Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
  • Gavva NR; Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
  • Lehto SG; Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
  • Geuns-Meyer S; Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
Bioorg Med Chem Lett ; 24(15): 3464-8, 2014 Aug 01.
Article em En | MEDLINE | ID: mdl-24953819
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Bloqueadores dos Canais de Cálcio / Desenho de Fármacos / Canais de Potencial de Receptor Transitório / Canais de Cátion TRPC / Compostos Heterocíclicos com 3 Anéis / Proteínas do Tecido Nervoso Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Bloqueadores dos Canais de Cálcio / Desenho de Fármacos / Canais de Potencial de Receptor Transitório / Canais de Cátion TRPC / Compostos Heterocíclicos com 3 Anéis / Proteínas do Tecido Nervoso Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2014 Tipo de documento: Article