RESUMO
Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (s.c. 60 mg/kg).
Assuntos
Antidepressivos/síntese química , Pirazinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Sítios de Ligação , Ligação Competitiva , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologiaRESUMO
A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC(50) 37 nM, solubility 14 microM), the most potent GlyT1 inhibitor in this series. Favorable brain-plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration.
Assuntos
Azetidinas/química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Sulfonamidas/química , Animais , Azepinas/química , Azetidinas/síntese química , Azetidinas/farmacocinética , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , BenzenossulfonamidasRESUMO
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; µ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; µ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.