RESUMEN

Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.

Asunto(s)

Compuestos Heterocíclicos con 3 Anillos/síntesis química , Pirazoles/síntesis química , Piridinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Acenaftenos , Hormona Adrenocorticotrópica/biosíntesis , Animales , Células Cultivadas , Hormona Liberadora de Corticotropina/metabolismo , AMP Cíclico/biosíntesis , Diseño de Fármacos , Femenino , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Conformación Molecular , Adenohipófisis/citología , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad