3-(4-phenoxyphenyl)pyrazoles: a novel class of sodium channel blockers

J Med Chem. 2004 Mar 11;47(6):1547-52. doi: 10.1021/jm030498q.

Abstract

A series of 3-(4-phenoxyphenyl)-1H-pyrazoles were synthesized and characterized as potent state-dependent sodium channel blockers. A limited SAR study was carried out to delineate the chemical requirements for potency. The results indicate that the distal phenyl group is critical for activity but will tolerate lipophilic (+pi) electronegative (+sigma) substituents at the ortho and/or para position. Substitution at the pyrazole nitrogen with a H-bond donor improves potency. Compound 18 showed robust activity in the rat Chung neuropathy paradigm.

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Cell Line
  • Humans
  • Male
  • Pain / drug therapy
  • Pain / etiology
  • Patch-Clamp Techniques
  • Peripheral Nervous System Diseases / complications
  • Peripheral Nervous System Diseases / drug therapy
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / chemical synthesis*
  • Sodium Channel Blockers / chemistry
  • Sodium Channel Blockers / pharmacology
  • Structure-Activity Relationship

Substances

  • 3-(4-(4-nitrophenoxy)phenyl)-1H-pyrazole-1-carboxamide
  • Analgesics
  • Pyrazoles
  • Sodium Channel Blockers