A stereoselective approach to peptidomimetic BACE1 inhibitors

Abstract

Aiming at identifying new scaffolds to generate beta-secretase (BACE1) inhibitors we developed peptidomimetics based on a 1,4-benzodiazepine core (3a-d), their seco-analogs (4a-b), and linear analogs (5a-h), by stereoselective approaches. We herein discuss the synthesis, molecular modeling and in vitro studies for the newly developed ligands. Compounds 5c and 5h behaved as BACE1 inhibitors on the isolated enzyme and in cellular studies. Particularly, for its low molecular weight, inhibitor 5h is a prototypic hit to develop a series of BACE1 inhibitors more potent and active on whole-cells.

Keywords: 1,4-benzodiazepine; AD; APP; Alzheimer's disease; BACE1; BDZ; Benzodiazepines; HEA; Inhibitors; Peptidomimetics; amyloid precursor protein; hydroxyethylamine; β-Secretase.