RESUMEN
Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate receptors. The structure-activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca2+ influx assay (IC50=60 nM) and in an in vivo AMPA-induced seizure model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy.
Asunto(s)
Descubrimiento de Drogas , Piridonas/química , Piridonas/farmacología , Receptores AMPA/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Semivida , Ensayos Analíticos de Alto Rendimiento , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Nitrilos , Piridonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
This paper describes the design, synthesis, and structure-activity relationships of a novel series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives for use as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor. The most promising compound, N-butyl-3-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[5,1-b][1,3]thiazole-7-amine (6t), showed high affinity (IC(50) = 70 nM) and functional antagonism (IC(50) = 7.1 nM) for the human CRF(1) receptor as well as dose-dependent inhibition of the CRF-induced increase in the plasma adrenocorticotropic hormone (ACTH) concentration at a dose of 30 mg/kg (po). Further, in the light/dark test in mice, the compound 6t showed anxiolytic activity at a dose of 30 mg/kg (po).
Asunto(s)
Ansiolíticos/síntesis química , Pirazoles/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Hormona Adrenocorticotrópica/sangre , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Línea Celular Tumoral , Hormona Liberadora de Corticotropina/farmacología , AMP Cíclico/metabolismo , Defecación/efectos de los fármacos , Diseño de Fármacos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Pirazoles/química , Pirazoles/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Design, synthesis, and structure-activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. It has advanced into clinical trials.