Structure-Based Design of Selective β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2

BACE1
inhibitors hold potential as agents in disease-modifying
treatment for Alzheimer’s disease. BACE2 cleaves the melanocyte
protein PMEL in pigment cells of the skin and eye, generating melanin
pigments. This role of BACE2 implies that nonselective and chronic
inhibition of BACE1 may cause side effects derived from BACE2. Herein,
we describe the discovery of potent and selective BACE1 inhibitors
using structure-based drug design. We targeted the flap region, where
the shape and flexibility differ between these enzymes. Analysis of
the cocrystal structures of an initial lead 8 prompted
us to incorporate spirocycles followed by its fine-tuning, culminating
in highly selective compounds 21 and 22.
The structures of 22 bound to BACE1 and BACE2 revealed
that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency,
thereby leading to its high selectivity. These findings and insights
should contribute to responding to the challenges in exploring selective
BACE1 inhibitors.