Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer's Agents Based on Rational Design.
J Med Chem
; 60(6): 2573-2590, 2017 03 23.
Article
em En
| MEDLINE
| ID: mdl-28234463
ABSTRACT
Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of ß-amyloid peptides (pGlu-Aß) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aß3E-42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aß and total Aß and restored cognitive functions. This potent Aß-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Peptídeos beta-Amiloides
/
Aminoaciltransferases
/
Inibidores Enzimáticos
/
Doença de Alzheimer
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2017
Tipo de documento:
Article