Structure-activity relationship study on the P4 structure of macrocyclic BACE1 inhibitors

-Secretase (BACE1) is an aspartic protease involved in the production of amyloid peptide (A).A accumulation in the brain is hypothesized to underlie the pathogenesis of Alzheimer's disease (AD), hence it is reasoned that inhibiting BACE1 will play a crucial role in the treatment of AD.Previously, we have synthesized and evaluated peptidic BACE1 inhibitors containing a hydroxyethylamine (HEA) type isostere 1,2 and discovered a macrocyclic inhibitor, inhibitor 3, containing a hydrophobic bridge between the P1 and P3 side chains 3 .Despite displaying good activity, the membrane permeability of inhibitor 3 is constrained by high hydrophilicity, limiting its development as a drug.Therefore, we try to design macrocyclic derivatives of this inhibitor with lower hydrophilicity, to increase membrane permeability.In this study, the amino and carboxy groups of glutamic acid at the P4 position of inhibitor 3 significantly influence its hydrophilicity, hence some derivatives of inhibitor 3 with a less hydrophilic substituent at the P4 position were designed and synthesized, and their activities were evaluated.