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

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived ß-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 (IC(50)=21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound ß-secretase. The model suggested possible interactions in the active site.