The
two proteases, beta- and gamma-secretase, that produce the amyloid
beta-peptide (A-beta) of Alzheimer's disease (AD) are top targets for
therapeutic intervention. However, potent beta-secretase inhibitors possess
poor physicochemical and pharmacokinetic properties, and gamma-secretase
inhibitors cause serious toxicities in mice due to deficiencies in Notch
signaling. Therefore, compounds with better drug-like properties that
selectively lower A-beta production while leaving Notch proteolysis intact
would be highly desirable. We have discovered two types of agents that
possess these properties. The first are small and structurally simple
compounds that interact directly with the gamma-secretase complex in
biochemical assays to allosterically modify substrate specificity at micromolar
concentration. The second are compounds, from a well known class of drugs,
that were discovered via a high-throughput screen using a cell-based reporter
assay; these apparently lower A-beta production through an indirect but
unknown mechanism at low nanomolar concentration. We propose (1) to carry out
structure-activity studies to improve potency while retaining selectivity,
(2) to determine the in vitro metabolic stability of potent and selective
compounds, and (3) to test the ability of the most promising compounds to
lower A-beta in an AD transgenic mouse model.