Development of novel azabenzofuran TRPA1 antagonists as in vivo tools

Katrina W Copeland; Alessandro A Boezio; Eugene Cheung; Josie Lee; Philip Olivieri; Laurie B Schenkel; Qian Wan; Weiya Wang; Mary C Wells; Beth Youngblood; Narender R Gavva; Sonya G Lehto; Stephanie Geuns-Meyer

doi:10.1016/j.bmcl.2014.05.069

Development of novel azabenzofuran TRPA1 antagonists as in vivo tools

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3464-8. doi: 10.1016/j.bmcl.2014.05.069. Epub 2014 Jun 6.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. Electronic address: kwoodin@amgen.com.
² Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. Electronic address: aboezio@amgen.com.
³ Department of Pharmaceutics, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
⁴ Department of Neuroscience, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
⁵ Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
⁶ Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
⁷ Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.

PMID: 24953819
DOI: 10.1016/j.bmcl.2014.05.069

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.

Keywords: Ion channel; Pain; TRPA1 antagonist.

MeSH terms

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
TRPA1 Cation Channel
TRPC Cation Channels / antagonists & inhibitors*
TRPC Cation Channels / metabolism
Transient Receptor Potential Channels / antagonists & inhibitors*
Transient Receptor Potential Channels / metabolism

Substances

Calcium Channel Blockers
Calcium Channels
Heterocyclic Compounds, 3-Ring
Isothiocyanates
Nerve Tissue Proteins
TRPA1 Cation Channel
TRPA1 protein, human
TRPC Cation Channels
Transient Receptor Potential Channels
Trpa1 protein, rat
allyl isothiocyanate