RESUMEN
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.
Asunto(s)
Compuestos de Bifenilo/química , Neuralgia/tratamiento farmacológico , Pirazoles/química , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/química , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/uso terapéutico , Perros , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Actividad Motora/efectos de los fármacos , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismoRESUMEN
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.
Asunto(s)
Alcaloides/farmacología , Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Menispermaceae/química , Oxadiazoles/farmacología , Pirrolidinas/farmacología , Alcaloides/química , Antivirales/química , Línea Celular , Cromatografía por Intercambio Iónico , Antígenos de Superficie de la Hepatitis B/metabolismo , Antígenos e de la Hepatitis B/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Oxadiazoles/química , Pirrolidinas/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
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.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Pirrolidinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Humanos , Macaca mulatta , Pirrolidinas/farmacocinética , Especificidad de la EspecieRESUMEN
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.