title: A peripherally acting Na(v)1.7 sodium channel blocker reverses hyperalgesia and allodynia on rat models of inflammatory and neuropathic pain.
abstract: BACKGROUND
  Voltage-gated sodium channels (Na(v)1) are expressed in primary sensory neurons where they influence excitability via their role in the generation and propagation of action potentials. Recently, human genetic data have shown that one sodium channel subtype, Na(v)1.7, plays a major role in pain. We performed these studies to characterize the antinociceptive effects of N-[(R)-1-((R)-7-chloro-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)-2-(2-fluorophenyl)-ethyl]-4-fluoro-2-trifluoromethyl-benzamide (BZP), a non-central nervous system (CNS) penetrant small molecule with high affinity and preferential selectivity for Na(v)1.7 over Na(v)1.8 and Na(v)1.5.
  
  
  METHODS
  BZP was evaluated in rat preclinical models of inflammatory and neuropathic pain and compared with standard analgesics. Two models were used: the complete Freund's adjuvant model of inflammatory pain and the spinal nerve ligation model of neuropathic pain. BZP was also evaluated in a motor coordination assay to assess its propensity for CNS side effects.
  
  
  RESULTS
  In preclinical models of chronic pain, BZP displayed efficacy comparable with that of leading analgesics. In the complete Freund's adjuvant model, BZP produced reversal of hyperalgesia comparable with nonsteroidal antiinflammatory drugs, and in the spinal nerve ligation model, BZP produced reversal of allodynia comparable with gabapentin and mexiletine. Unlike the CNS penetrant compounds gabapentin and mexiletine, BZP did not induce any impairment of motor coordination.
  
  
  CONCLUSIONS
  These data suggest that a peripherally acting sodium channel blocker, preferentially acting through Na(v)1.7, could provide clinical relief of chronic pain without the CNS side effects typical of many existing pain treatments.
authors.affiliation: Merck Research Laboratories, Department of Pharmacology and Medicinal Chemistry, Rahway, New Jersey, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: McGowan
authors.forename: Scott B
authors.initials: SB
authors.lastname: Hoyt
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.forename: Catherine
authors.initials: C
authors.lastname: Abbadie
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D006930:Hyperalgesia / Q000473:pathology; D007249:Inflammation; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009410:Nerve Degeneration / Q000473:pathology; D010146:Pain; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism*; D013127:Spinal Nerves / Q000473:pathology
chemical_list: D000700:Analgesics; D001549:Benzamides; C543349:N-((R)-1-((R)-7-chloro-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)azepin-3-ylcarbamoyl)-2-(2-fluorophenyl)ethyl)-4-fluoro-2-trifluoromethyl-benzamide; D062556:NAV1.7 Voltage-Gated Sodium Channel; C503480:Scn9a protein, rat; D015222:Sodium Channels