Design, synthesis and SAR of a new class of small molecule inhibitors of β-Secretase.

β-Secretase is the enzyme responsible for the Amyloid-β plaques found in Alzheimer’s disease. Inhibition of this enzyme should prove to be very useful in combating Alzheimer’s disease by preventing this build-up. After a computational screening of the NCID-2 library a molecule was found to possess a 2- propanol structure with aromatic groups on either side. This moiety was replicated by a combinatorial library of 150 compounds. These compounds were screened initially against β-secretase at 100, 50, and then 25 μM to narrow down to 17 structures showing 50% inhibition at 25 μM. The IC50 for each of the 17 molecules was found experimentally resulting in one lead compound 15, 4.93 μM ± 0.86 μM. This compound was modified by making slight changes to the 2-propanol moiety resulting in mostly loss of activity