RESUMEN

Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3 mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.

Asunto(s)

Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacocinética , Animales , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Semivida , Humanos , Microsomas/metabolismo , Modelos Animales , Ratas , Relación Estructura-Actividad

RESUMEN

Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.

Asunto(s)

Antidepresivos/síntesis química , Antidepresivos/farmacocinética , Antagonistas de los Receptores de Hormonas Antidiuréticas , Indoles/síntesis química , Indoles/farmacocinética , Animales , Antidepresivos/química , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Indoles/química , Indoles/farmacología , Estructura Molecular , Oxindoles , Unión Proteica/efectos de los fármacos , Ratas