Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position

Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of these inhibitors, we found that the σ–π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position are described along with the results of the related structure–activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide