Naphthyl and Coumarinyl Biarylpiperazine Derivatives as Highly Potent Human β-Secretase Inhibitors. Design, Synthesis, and Enzymatic BACE-1 and Cell Assays
Résumé
Twenty novel â-secretase inhibitors containing biarylpiperazine moieties belonging to naphthyl and coumarinyl
series were designed for their potential use in Alzheimer’s disease therapy. Enzymatic and cell-based assays
have been carried out. The biological results clearly demonstrate that specific substituents located at the
N4-position of the piperazine ring result in excellent in vitro inhibitory potency (IC50 values ranging between
40 and 70 nM). Variable temperature NMR and modeling studies are consistent with the obtained biological
data, since these studies confirmed that introduction at the N4-position of the piperazine ring allows productive
interactions within the BACE-1 active site, which appear to be determinative for high BACE-1 inhibitory
activity. These results are of particular interest since some of the new analogues belonging to the naphthyl
series are almost one log more active than the best inhibitor of the similar family recently reported.