RESUMO
The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.
Assuntos
Aminas/síntese química , Inibidores da Captação de Dopamina , Desenho de Fármacos , Metano/síntese química , Norepinefrina , Serotonina , Aminas/química , Aminas/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Ciclização , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/farmacologia , Concentração Inibidora 50 , Metano/química , Metano/farmacologia , Camundongos , Estrutura Molecular , Norepinefrina/síntese química , Norepinefrina/química , Norepinefrina/farmacologia , Ratos , Serotonina/síntese química , Serotonina/química , Serotonina/farmacologia , EstereoisomerismoRESUMO
Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC(50) ≤ 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.
Assuntos
Aminas/síntese química , Inibidores da Captação de Dopamina , Desenho de Fármacos , Norepinefrina , Serotonina , Aminas/química , Aminas/farmacologia , Animais , Ciclização , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/farmacologia , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Norepinefrina/síntese química , Norepinefrina/química , Norepinefrina/farmacologia , Serotonina/síntese química , Serotonina/química , Serotonina/farmacologia , EstereoisomerismoRESUMO
The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.
Assuntos
Naftalenos/síntese química , Naftalenos/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Modelos Animais de Doenças , Dopamina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Camundongos , Norepinefrina/metabolismo , Serotonina/metabolismoRESUMO
The present work expands the chemical space known to offer potent inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) and discloses novel bicyclic octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindole scaffolds as potent triple reuptake inhibitors (TRIs) for the potential treatment of depression. Optimized compounds 22a (SERT, NET, DAT, IC(50) = 20, 109, 430 nM), 23a (SERT, NET, DAT, IC(50) = 29, 85, 168 nM), and 26a (SERT, NET, DAT, IC(50) = 53, 150, 140 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 10 and 30 mpk PO, and were not generally motor stimulants at doses ranging from 1 to 30 mpk PO. Moderate in vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG) inhibition were uncovered as potential liabilities for the chemical series.