RESUMEN
The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.
Asunto(s)
Pirazinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Tejido Adiposo/metabolismo , Administración Oral , Hormona Adrenocorticotrópica/sangre , Animales , Disponibilidad Biológica , Barrera Hematoencefálica/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Humanos , Técnicas In Vitro , Inyecciones Intraventriculares , Masculino , Microsomas Hepáticos/metabolismo , Actividad Motora/efectos de los fármacos , Pirazinas/química , Pirazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Restricción Física , Relación Estructura-ActividadRESUMEN
The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.
Asunto(s)
Química Farmacéutica/métodos , Pirimidinas/química , Pirimidinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Sitios de Unión , Química Farmacéutica/instrumentación , Diseño de Fármacos , Humanos , Cinética , Modelos Químicos , Conformación Molecular , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.
