BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres

A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.

Graphical abstractA new class of β-secretase inhibitors that incorporate a reduced amide transition state isostere as the key binding element is described. The incorporation of a 5-substituted isophthalamide scaffold at the N-terminal site of this isostere resulted in potent compounds that display impressive cellular IC50 values. The syntheses and BACE-1 activities of these inhibitors are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide