title: A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability.
abstract: OBJECTIVE
  NaV 1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav 1.8 channel blocker of novel chemotype.
  
  
  METHODS
  The inhibition of Nav 1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain.
  
  
  RESULTS
  PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50 : 331 nM) and in recombinantly expressed h Nav 1.8 channels (IC50 : 196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav 1.5 channels (IC50 : ∼10 μM) and 65-100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50 : ∼10-18 μM). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448 nM, and the block of both human recombinant Nav 1.8 channels and TTX-R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF-01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models.
  
  
  CONCLUSIONS
  Using PF-01247324, we have confirmed a role for Nav 1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav 1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.
authors.affiliation: Neusentis UK, Pfizer Global R&D, Cambridge, UK.
authors.forename: Claire Elizabeth
authors.initials: CE
authors.lastname: Payne
authors.forename: Adam R
authors.initials: AR
authors.lastname: Brown
authors.forename: Jonathon W
authors.initials: JW
authors.lastname: Theile
authors.forename: Alexandre J C
authors.initials: AJ
authors.lastname: Loucif
authors.forename: Aristos J
authors.initials: AJ
authors.lastname: Alexandrou
authors.forename: Mathew D
authors.initials: MD
authors.lastname: Fuller
authors.forename: John H
authors.initials: JH
authors.lastname: Mahoney
authors.forename: Brett M
authors.initials: BM
authors.lastname: Antonio
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Gerlach
authors.forename: David M
authors.initials: DM
authors.lastname: Printzenhoff
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Prime
authors.forename: Gillian
authors.initials: G
authors.lastname: Stockbridge
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kirkup
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bannon
authors.forename: Steve
authors.initials: S
authors.lastname: England
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chapman
authors.forename: Sharan
authors.initials: S
authors.lastname: Bagal
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Roeloffs
authors.forename: Uma
authors.initials: U
authors.lastname: Anand
authors.forename: Praveen
authors.initials: P
authors.lastname: Anand
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bungay
authors.forename: Mark
authors.initials: M
authors.lastname: Kemp
authors.forename: Richard P
authors.initials: RP
authors.lastname: Butt
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stevens
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000187:drug effects; D059225:Nociception / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D010848:Picolinic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: C000607773:6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxylic acid methylamide; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010848:Picolinic Acids; C568317:SCN10A protein, human; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin