Design and synthesis of potent, orally efficacious hydroxyethylamine derived ß-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.
J Med Chem
; 55(21): 9025-44, 2012 Nov 08.
Article
em En
| MEDLINE
| ID: mdl-22468684
ABSTRACT
We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-ß peptide (Aß) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Aß levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Compostos de Espiro
/
Tiazóis
/
Peptídeos beta-Amiloides
/
Ácido Aspártico Endopeptidases
/
Secretases da Proteína Precursora do Amiloide
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos