Modular synthesis of 2,4-diaminoanilines as CNS drug-like non-covalent inhibitors of asparagine endopeptidase.
Bioorg Med Chem
; 63: 116746, 2022 06 01.
Article
en En
| MEDLINE
| ID: mdl-35430537
ABSTRACT
Asparagine endopeptidase (AEP), also called legumain, is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Recent studies showed that it possesses δ-secretase activity and that it is implicated in numerous neurological diseases such as Alzheimer's disease (AD). Following evidence of aryl-morpholines as useful asparagine endopeptidase inhibitors, a series of morpholinoanilines with diverse substituents at ortho position were synthesized in view of improving the potency and scope of this molecular scaffold, allowing to identify ethyl 2-isonipecotate-4-morpholinoaniline possessing inhibition potency in the nanomolar range. CNS MPO (CNS MultiParameter Optimization) calculations revealed that most of the compounds developed in this work show physicochemical parameters in the desirable range for CNS drug candidates.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cisteína Endopeptidasas
/
Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Italia