Novel non-peptidic and small-sized BACE1 inhibitors

Recently, we reported substrate-based β-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activities ( 1.2 nM IC50). In order to improve in vivo enzymatic stability and permeability across the blood–brain barrier, these penta-peptidic inhibitors would need to be further optimized. On the other hand, non-peptidic inhibitors possessing isophthalic residue at the P2 position were reported from other research groups. We selected isophthalic-type aromatic residues at the P2 position and an HMC isostere at the P1 position as lead compounds. On the basis of the design approach focused on the conformer of docked inhibitor in BACE1, we found novel non-peptidic and small-sized BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic, chelidamic or chelidonic residue at the P2 position.