RESUMO
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.
Assuntos
Analgésicos/síntese química , Piridinas/síntese química , Bloqueadores dos Canais de Sódio/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Linhagem Celular , Humanos , Técnicas In Vitro , Masculino , Canal de Sódio Disparado por Voltagem NAV1.2 , Proteínas do Tecido Nervoso/antagonistas & inibidores , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor , Doenças do Sistema Nervoso Periférico/fisiopatologia , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio , Relação Estrutura-AtividadeRESUMO
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.