Novel non-peptidic and small-sized BACE1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.01.056

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.