RESUMEN
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Asunto(s)
Pteridinas/química , Pirazinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Semivida , Pteridinas/síntesis química , Pteridinas/farmacocinética , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/síntesis química , Proteínas Activadoras de la 5-Lipooxigenasa/química , Alcanos/síntesis química , Antialérgicos/síntesis química , Derivados del Benceno/síntesis química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Alcanos/farmacocinética , Alcanos/farmacología , Animales , Antialérgicos/farmacocinética , Antialérgicos/farmacología , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.