Highly Selective and Potent Human ß-Secretaseâ
2 (BACE2) Inhibitors against Typeâ
2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies.
ChemMedChem
; 14(5): 545-560, 2019 03 05.
Article
en En
| MEDLINE
| ID: mdl-30637955
ABSTRACT
Herein we present the design, synthesis, and biological evaluation of potent and highly selective ß-secretaseâ
2 (memapsinâ
1, beta-site amyloid precursor protein cleaving enzymeâ
2, or BACE 2) inhibitors. BACE2 has been recognized as an exciting new target for typeâ
2 diabetes. The X-ray structure of BACE1 bound to inhibitor 2 a {N3 -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)propyl]amino]propyl]-5-[methyl(methylsulfonyl)amino]-N1 -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide} containing a hydroxyethylamine isostere was determined. Based on this structure, a computational docking study was performed which led to inhibitor 2 a-bound BACE2 models. These were used to optimize the potency and selectivity of inhibitors. A systematic structure-activity relationship study led to the identification of determinants of the inhibitors' potency and selectivity toward the BACE2 enzyme. Inhibitors 2 d [N3 -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)pentyl]amino]propyl]-N1 -methyl-N1 -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide; Ki =0.031â
nm, selectivity over BACE1 ≈174 000-fold] and 3 l [N1 -((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N3 ,5-dimethyl-N3 -((R)-1-phenylethyl)isophthalamide; Ki =1.6â
nm, selectivity over BACE1 >500-fold] displayed outstanding potency and selectivity. Inhibitor 3 l is nonpeptide in nature and may pave the way to the development of a new class of potent and selective BACE2 inhibitors with clinical potential.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ácido Aspártico Endopeptidasas
/
Diabetes Mellitus Tipo 2
/
Inhibidores Enzimáticos
/
Etilaminas
/
Secretasas de la Proteína Precursora del Amiloide
/
Hipoglucemiantes
Límite:
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos