RESUMEN
The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/química , Modelos Moleculares , Péptidos/química , Ácidos Ftálicos/síntesis química , Precursor de Proteína beta-Amiloide/química , Línea Celular , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Imitación Molecular , Estructura Molecular , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacología , EstereoisomerismoRESUMEN
The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.
Asunto(s)
Amidas/síntesis química , Ácido Aspártico Endopeptidasas/química , Dipéptidos/química , Etilenos/síntesis química , Ácidos Ftálicos/síntesis química , Inhibidores de Proteasas/síntesis química , Amidas/química , Secretasas de la Proteína Precursora del Amiloide , Diseño de Fármacos , Endopeptidasas , Etilenos/química , Humanos , Modelos Moleculares , Imitación Molecular , Ácidos Ftálicos/química , Inhibidores de Proteasas/química , Relación Estructura-ActividadRESUMEN
By use of the effectively cleaved beta-secretase (BACE) substrate (1), incorporation of a statine in P(1) resulted in a weak inhibitor 13 of the enzyme. Further substitution of P(1)'-Asp by P(1)'-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P(10)-P(5) residues on the N-terminal part of inhibitor 22 resulted in no loss of potency (23). C-terminal truncations of inhibitor 22 generally led to significant loss of potency.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Oligopéptidos/síntesis química , Secretasas de la Proteína Precursora del Amiloide , Encéfalo/enzimología , Endopeptidasas , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Oligopéptidos/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.