Design, synthesis, and evaluation of Leu∗Ala hydroxyethylene-based non-peptide β-secretase (BACE) inhibitors Original Research Article

With the aim of developing small molecular non-peptide β-secretase (BACE) inhibitors, Leu∗Ala hydroxyethylene (HE) was investigated as a scaffold to design and synthesize a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modeling, extensive structure–activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the Leu∗Ala HE scaffold. Isobutyl amine was found to be an optimal C-cap, and suitable hydroxylalkylamines at the 3-position and nitro or methyl(methylsulfonyl)amine at the 5-position of isophthalamide as the N-terminus could form additional hydrogen bonds with BACE active sites and help improve potency. Many new potent non-peptide BACE inhibitors were identified in this study. Among them, compounds 37 and 44 exhibited excellent enzyme-inhibiting potency, comparable to that of OM99-2, and obvious inhibitory effects in cell-based assay with low molecular weights (<600).