RESUMEN
On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.
Asunto(s)
Piperazinas/síntesis química , Quinolinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas de la Serotonina/síntesis química , Animales , Antidepresivos/farmacología , Células CHO , Cricetinae , Cricetulus , Inhibidores Enzimáticos del Citocromo P-450 , Humanos , Microdiálisis , Piperazinas/farmacología , Quinolinas/farmacología , Ratas , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Dopaminérgicos/metabolismo , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Small molecule agonists and antagonists of the V(2)-vasopressin receptor have been discovered and have undergone clinical trials. In conjunction with these discovery programs, the synthesis and biological testing of various metabolites associated with these clinical targets were actively pursued. We now report the results of our synthetic efforts and the corresponding biological data generated for several of the metabolites of WAY-151932 and CL-347985 (Lixivaptan).
