Potent memapsin 2 (β-secretase) inhibitors: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation

Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic β-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (Ki 1.8 nM) and cellular (IC50 = 1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma Aβ) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.