1,4-Oxazine β‑Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads

1,4-Oxazines
are presented, which show good in vitro inhibition
in enzymatic and cellular BACE1 assays. We describe lead optimization
focused on reducing the amidine pKa while
optimizing interactions in the BACE1 active site. Our strategy permitted
modulation of properties such as permeation and especially P-glycoprotein
efflux. This led to compounds which were orally bioavailable, centrally
active, and which demonstrated robust lowering of brain and CSF Aβ
levels, respectively, in mouse and dog models. The amyloid lowering
potential of these molecules makes them valuable leads in the search
for new BACE1 inhibitors for the treatment of Alzheimer’s disease.