RESUMO
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.
Assuntos
Piperazinas/síntese química , Quinolinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/síntese química , Animais , Antidepressivos/farmacologia , Células CHO , Cricetinae , Cricetulus , Inibidores das Enzimas do Citocromo P-450 , Humanos , Microdiálise , Piperazinas/farmacologia , Quinolinas/farmacologia , Ratos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Dopaminérgicos/metabolismo , Antagonistas da Serotonina/farmacocinética , Antagonistas da Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
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).