title: Selective antagonism of TRPA1 produces limited efficacy in models of inflammatory- and neuropathic-induced mechanical hypersensitivity in rats.
abstract: The transient receptor potential ankyrin 1 (TRPA1) channel has been implicated in pathophysiological processes that include asthma, cough, and inflammatory pain. Agonists of TRPA1 such as mustard oil and its key component allyl isothiocyanate (AITC) cause pain and neurogenic inflammation in humans and rodents, and TRPA1 antagonists have been reported to be effective in rodent models of pain. In our pursuit of TRPA1 antagonists as potential therapeutics, we generated AMG0902, a potent (IC90of 300 nM against rat TRPA1), selective, brain penetrant (brain to plasma ratio of 0.2), and orally bioavailable small molecule TRPA1 antagonist. AMG0902 reduced mechanically evoked C-fiber action potential firing in a skin-nerve preparation from mice previously injected with complete Freund's adjuvant, supporting the role of TRPA1 in inflammatory mechanosensation. In vivo target coverage of TRPA1 by AMG0902 was demonstrated by the prevention of AITC-induced flinching/licking in rats. However, oral administration of AMG0902 to rats resulted in little to no efficacy in models of inflammatory, mechanically evoked hypersensitivity; and no efficacy was observed in a neuropathic pain model. Unbound plasma concentrations achieved in pain models were about 4-fold higher than the IC90concentration in the AITC target coverage model, suggesting that either greater target coverage is required for efficacy in the pain models studied or TRPA1 may not contribute significantly to the underlying mechanisms.
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA slehto@amgen.com.
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.affiliation: School of Physical Therapy, Pacific University, Hillsboro, OR, USA.
authors.forename: Andy D
authors.initials: AD
authors.lastname: Weyer
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Beth D
authors.initials: BD
authors.lastname: Youngblood
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Ruoyuan
authors.initials: R
authors.lastname: Yin
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.affiliation: Department of Pharmaceutics, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Cooke
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Stucky
authors.affiliation: Medicinal Chemistry, Amgen Inc, Cambridge, MA, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Schenkel
authors.affiliation: Medicinal Chemistry, Amgen Inc, Cambridge, MA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Geuns-Meyer
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Moyer
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Wild
authors.affiliation: Department of Neuroscience, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000588:Amines / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects; D005620:Freund's Adjuvant / Q000633:toxicity; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009288:Naproxen / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012585:Sciatica / Q000150:complications* / Q000188:drug therapy; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use
chemical_list: D000588:Amines; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003509:Cyclohexanecarboxylic Acids; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D005680:gamma-Aminobutyric Acid; D009288:Naproxen; D000077206:Gabapentin; D005620:Freund's Adjuvant
keywords: AMG0902; TRPA1; inflammatory; neuropathic; pain; rat