Inhibition of BACE1 to prevent brain A尾 peptide for
mation is a potential disease-
modifying approach to the treat
ment of Alzhei
mer鈥檚 disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS A尾 levels following syste
mic ad
ministration re
mains challenging. In this report we describe structure-based opti
mization of a series of brain-penetrant BACE1 inhibitors derived fro
m an i
minopyri
midinone scaffold. Application of structure-based design in tande
m with control of physicoche
mical properties cul
minated in the discovery of co
mpound
16, which potently reduced cortex and CSF A尾40 levels when ad
ministered orally to rats.
Keywords:
BACE1; inhibitor; mer%E2%80%99s+disease&qsSearchArea=searchText">Alzheimer鈥檚 disease; A尾40; minopyrimidinone&qsSearchArea=searchText">iminopyrimidinone; X-ray crystallography