Discovery of Extremely Selective Fused Pyridine-Derived β‑Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions

β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1)
is considered to be a promising target for treating Alzheimer’s
disease. However, all clinical BACE1 inhibitors have failed due to
lack of efficacy, and some have even led to cognitive worsening. Recent
evidence points to the importance of avoiding BACE2 inhibition along
with careful dose titration. In this study, we focused on the fact
that the 10s loop lining the S3 pocket in BACE1 can form both “open
(up)” and “closed (down)” conformations, whereas
in BACE2, it prefers to adopt a “closed” form; thus,
more space is available in BACE1. By leveraging the difference, we
designed fused pyridine analogues that could reach the 10s loop, leading
to 6 with high selectivity and significant Aβ reduction.
The cocrystal structures confirmed that 6 significantly
increased B-factors of the 10s loop in BACE2 relative to those in
BACE1. Thus, the destabilization of BACE2 seems to offer structural
insights into the reduced BACE2 potency of 6, explaining
the significant improvement in BACE1 selectivity.