Potent Memapsin 2 (β-Secretase) Inhibitors: Design Synthesis Protein-Ligand X-ray Structure and in vivo Evaluation

摘要

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 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 complexes of memapsin 2 revealed critical interactions in the memapsin 2 active site.