Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand

We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a–h) or a thiazole moiety (compounds 4a–e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki = 0.25 nM, cellular EC50 of 194 nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site.

β-Secretase inhibitor 4c showed an enzyme Ki of 0.25 nM and a cellular EC50 value of 194 nM. A molecular model of 4c provided insight into the ligand-binding site interactions.Figure optionsDownload as PowerPoint slide