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