ABSTRACT
In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.
Subject(s)
Analgesics/chemical synthesis , Pyridines/chemical synthesis , Sodium Channel Blockers/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Animals, Newborn , Brain/metabolism , Cell Line , Humans , In Vitro Techniques , Male , NAV1.2 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/antagonists & inhibitors , Pain/drug therapy , Pain/physiopathology , Pain Measurement , Peripheral Nervous System Diseases/physiopathology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Sodium Channels , Structure-Activity RelationshipABSTRACT
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.