Rational Design of Novel 1,3-Oxazine Based β‑Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P‑gp Efflux Leading to Robust Aβ Reduction in the Brain

Accumulation of Aβ
peptides is a hallmark of Alzheimer’s
disease (AD) and is considered a causal factor in the pathogenesis
of AD. β-Secretase (BACE1) is a key enzyme responsible for producing
Aβ peptides, and thus agents that inhibit BACE1 should be beneficial
for disease-modifying treatment of AD. Here we describe the discovery
and optimization of novel oxazine-based BACE1 inhibitors by lowering
amidine basicity with the incorporation of a double bond to improve
brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a pKa lowering strategy to reduce the P-gp efflux
and the high hERG potential leading to the discovery of 15 that produced significant Aβ reduction with long duration
in pharmacodynamic models and exhibited wide safety margins in cardiovascular
safety models. This compound improved the brain-to-plasma ratio relative
to 6 by reducing P-gp recognition, which was demonstrated
by a P-gp knockout mouse model.