Chemistry Reference
In-Depth Information
11
Identification of High-affinity
-Secretase Inhibitors Using
Fragment-based Lead Generation
Jeffrey S. Albert and Philip D. Edwards
11.1
Introduction: BACE and Its Role in Alzheimer's Disease
A leading hypothesis for the pathophysiology of Alzheimer's disease centers on the abnor-
mal accumulation of plaques in the brain that are composed from the 40/42 amino acid
polypeptide called -amyloid peptide (A
40
/
42
). According to the amyloid cascade hypo-
thesis, -amyloid is produced in the brain as the product of two proteolytic processing
events; -amyloid precursor protein (APP) is cleaved first by -secretase (BACE) and then
by -secretase (Figure 11.1). Thus formed, the -amyloid peptide accumulates and deposits
as insoluble plaques that are either causative or otherwise associated with progression of
Alzheimer's disease.
[
1
]
According to this model, BACE is a particularly attractive target for
Alzheimer's disease therapy because inhibition should reduce -amyloid production. The
safety of BACE inhibitors is supported by the observation that BAC
E
-knockout mice appear
normal except for their inability to produce the -amyloid peptide.
[
2 6
]
Five research groups
independently identified BACE in 1999.
[
7 11
]
Since then, intense effort has been inves
t
ed
in discovering inhibitors for this enzyme. This area has been extensively reviewed.
[
1, 12 16
]
