ABSTRACT
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Subject(s)
Biphenyl Compounds/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/therapeutic use , Dogs , Drug Evaluation, Preclinical , Humans , Mice , Microsomes, Liver/metabolism , Motor Activity/drug effects , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolismABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Subject(s)
Neuralgia/drug therapy , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Animals , Dogs , Haplorhini , Humans , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.
