Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1.
Bioorg Med Chem Lett
; 28(6): 1043-1049, 2018 04 01.
Article
em En
| MEDLINE
| ID: mdl-29486970
ABSTRACT
A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10⯵mol/kg compared to control.
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Base de dados:
MEDLINE
Assunto principal:
Benzamidas
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Compostos Bicíclicos com Pontes
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Proteínas da Membrana Plasmática de Transporte de Glicina
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article