Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors.
Bioorg Med Chem
; 26(12): 3133-3144, 2018 07 23.
Article
em En
| MEDLINE
| ID: mdl-29705377
ABSTRACT
Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent AßN3pE-40-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer's agents.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aminoaciltransferases
/
Inibidores Enzimáticos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2018
Tipo de documento:
Article