RESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Modelos Moleculares , Peptídeos/química , Ácidos Ftálicos/síntese química , Precursor de Proteína beta-Amiloide/química , Linhagem Celular , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Mimetismo Molecular , Estrutura Molecular , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , EstereoisomerismoRESUMO
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.
Assuntos
Amidas/síntese química , Ácido Aspártico Endopeptidases/química , Dipeptídeos/química , Etilenos/síntese química , Ácidos Ftálicos/síntese química , Inibidores de Proteases/síntese química , Amidas/química , Secretases da Proteína Precursora do Amiloide , Desenho de Fármacos , Endopeptidases , Etilenos/química , Humanos , Modelos Moleculares , Mimetismo Molecular , Ácidos Ftálicos/química , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Aminoácidos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Oligopeptídeos/química , Aminoácidos/química , Aminoácidos/farmacologia , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Linhagem Celular , Endopeptidases , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Mimetismo Molecular , Relação Estrutura-AtividadeRESUMO
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.