ABSTRACT
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.
Subject(s)
Amides/chemical synthesis , Aspartic Acid Endopeptidases/chemistry , Dipeptides/chemistry , Ethylenes/chemical synthesis , Phthalic Acids/chemical synthesis , Protease Inhibitors/chemical synthesis , Amides/chemistry , Amyloid Precursor Protein Secretases , Drug Design , Endopeptidases , Ethylenes/chemistry , Humans , Models, Molecular , Molecular Mimicry , Phthalic Acids/chemistry , Protease Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
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.