RESUMEN
The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED(50) = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.
Asunto(s)
Ansiolíticos/síntesis química , Ansiolíticos/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/química , Estructura Molecular , Ratas , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained.
Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacocinética , Isoenzimas/antagonistas & inhibidores , Piridazinas/síntesis química , Animales , Línea Celular , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Edema/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Proteínas de la Membrana , Tasa de Depuración Metabólica , Prostaglandina-Endoperóxido Sintasas , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.
Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Furanos/síntesis química , Furanos/farmacología , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Células CHO , Fenómenos Químicos , Química Física , Cricetinae , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Edema/inducido químicamente , Edema/prevención & control , Fiebre/inducido químicamente , Fiebre/tratamiento farmacológico , Humanos , Proteínas de la Membrana , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Ratas , Solubilidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The COX-2 inhibitor DFP [5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone] was found to have a long half-life in humans. Analogues have been characterized in order to optimize pharmacokinetics. This has lead to the discovery of 5(S)-(5-ethyl-5-methyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone analogue 11 a potent and selective COX-2 inhibitor which is metabolized to a greater extent than DFP upon incubation with rat and human hepatocytes, suggesting a shorter half-life in humans.