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
The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK(1) antagonists in vitro and efficacious in vivo with minimal interactions with P(450) liver enzymes. Oxadiazole analog 22 was determined to have excellent hNK(1) binding affinity, functional activity, and a good PD response in vivo.
Assuntos
Alcaloides/farmacologia , Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Menispermaceae/química , Oxidiazóis/farmacologia , Pirrolidinas/farmacologia , Alcaloides/química , Antivirais/química , Linhagem Celular , Cromatografia por Troca Iônica , Antígenos de Superfície da Hepatite B/metabolismo , Antígenos E da Hepatite B/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Oxidiazóis/química , Pirrolidinas/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Pirrolidinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Humanos , Macaca mulatta , Pirrolidinas/farmacocinética , Especificidade da EspécieRESUMO
A series of 2-aminoquinoline compounds was prepared and evaluated in MCH1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl, and cyclic amines were tolerated at the quinoline 2-position. The in vivo efficacy of compound 12 was explored and compared to that of a related inactive analog to determine their effects on food intake and body weight in rodents.