RESUMO
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.
