Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived beta-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K-i = 13 nM) and cellular (IC50 = 21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound beta-secretase. The model suggested possible interactions in the active site. (C) 2012 Elsevier Ltd. All rights reserved.