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

摘要

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 po tent 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.