title: AMG2850, a potent and selective TRPM8 antagonist, is not effective in rat models of inflammatory mechanical hypersensitivity and neuropathic tactile allodynia.
abstract: TRPM8 has been implicated in pain and migraine based on dorsal root- and trigeminal ganglion-enriched expression, upregulation in preclinical models of pain, knockout mouse studies, and human genetics. Here, we evaluated the therapeutic potential in pain of AMG2850 ((R)-8-(4-(trifluoromethyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-5,6-dihydro-1,7-naphthyridine-7(8H)-carboxamide), a small molecule antagonist of TRPM8 by in vitro and in vivo characterization. AMG2850 is potent in vitro at rat TRPM8 (IC90 against icilin activation of 204 ± 28 nM), highly selective (>100-fold IC90 over TRPV1 and TRPA1 channels), and orally bioavailable (F po > 40 %). When tested in a skin-nerve preparation, AMG2850 blocked menthol-induced action potentials but not mechanical activation in C fibers. AMG2850 exhibited significant target coverage in vivo in a TRPM8-mediated icilin-induced wet-dog shake (WDS) model in rats (at 10 mg/kg p.o.). However, AMG2850 did not produce a significant therapeutic effect in rat models of inflammatory mechanical hypersensitivity or neuropathic tactile allodynia at doses up to 100 mg/kg. The lack of efficacy suggests that either TRPM8 does not play a role in mediating pain in these models or that a higher level of target coverage is required. The potential of TRPM8 antagonists as migraine therapeutics is yet to be determined.
authors: Department of Neuroscience, Amgen Inc, One Amgen Center Dr, Thousand Oaks, CA, 91320-1799, USA, slehto@amgen.com.
authors: Sonya G
authors: SG
authors: Lehto
authors: Andy D
authors: AD
authors: Weyer
authors: Maosheng
authors: M
authors: Zhang
authors: Beth D
authors: BD
authors: Youngblood
authors: Judy
authors: J
authors: Wang
authors: Weiya
authors: W
authors: Wang
authors: Patrick C
authors: PC
authors: Kerstein
authors: Carl
authors: C
authors: Davis
authors: Kenneth D
authors: KD
authors: Wild
authors: Cheryl L
authors: CL
authors: Stucky
authors: Narender R
authors: NR
authors: Gavva
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003080:Cold Temperature; D006224:Cricetinae; D003412:Cricetulus; D005620:Freund's Adjuvant; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D008610:Menthol / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000494:pharmacology* / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy; D011744:Pyrimidinones; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: C000603942:AMG2850; D009287:Naphthyridines; D011744:Pyrimidinones; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; D008610:Menthol; D005620:Freund's Adjuvant; C490483:icilin; D002118:Calcium