RESUMO
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.
Assuntos
Compostos de Bifenilo/química , Neuralgia/tratamento farmacológico , Pirazóis/química , Bloqueadores dos Canais de Sódio/química , Canais de Sódio/química , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/uso terapêutico , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Atividade Motora/efeitos dos fármacos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Bloqueadores dos Canais de Sódio/farmacocinética , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/metabolismoRESUMO
Numerous structurally and functionally unrelated drugs block the hERG potassium channel. HERG channels are involved in cardiac action potential repolarization, and reduced function of hERG lengthens ventricular action potentials, prolongs the QT interval in an electrocardiogram, and increases the risk for potentially fatal ventricular arrhythmias. In order to reduce the risk of investing resources in a drug candidate that fails preclinical safety studies because of QT prolongation, it is important to screen compounds for activity on hERG channels early in the lead optimization process. A number of hERG assays are available, ranging from high throughput binding assays on stably expressed recombinant channels to very time consuming electrophysiological examinations in cardiac myocytes. Depending on the number of compounds to be tested, binding assays or functional assays measuring membrane potential or Rb(+) flux, combined with electrophysiology on a few compounds, can be used to efficiently develop the structure-function relationship of hERG interactions.
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Antiarrítmicos/química , Descoberta de Drogas/métodos , Relação Estrutura-AtividadeRESUMO
A series of benzazepinones were synthesized and evaluated as hNa(v)1.7 sodium channel blockers. Several compounds from this series displayed good oral bioavailability and exposure and were efficacious in a rat model of neuropathic pain.