Letters
The AE motif represents a new class of BACE-1 inhibitor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 841
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pharmacophore, having an inherent binding affinity for the
catalytic site that is similar to the well established HE scaffold.
Although the enzymatic inhibition SAR trends and active site
binding position of the two isosteres tracked very closely with
one another, the cell-based activity was markedly better for the
AE compounds. While the source of this potency difference is
unclear, an obvious physicochemical difference is the expected
protonation, and hence more hydrophilic character, of the AE
inhibitors at neutral pH and in the more acidic cellular
compartments in which BACE-1 is localized. Recently reported
HEA inhibitors, also having an inherently more hydrophilic core
than HEs, have also shown high potency in cell-based assays.8
In summary, the combination of the AE isostere with
optimized replacements for the P2/P3 dipeptide, P2′ dipeptide,
and P1 side chain resulted in a compound, 7, that represents a
promising new series of BACE-1 inhibitors that is distinct from
others reported to date. Compound 7 displayed good enzymatic
and cell-based inhibitory potency, and a molecular weight below
600. Further improvement of these parameters and the incor-
poration of other drug-like properties into AE isostere inhibitors
are the subjects of ongoing efforts.
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Acknowledgment. We thank Stuart Lam and Heman Lee
for compound purifications, Dr. Mark Cancilla for mass
spectrometry measurements, and Drs. Sam Graham, Joe Vacca
and Adam Simon of Merck Research Laboratories at West Point,
PA, for critical reading of this manuscript. Portions of this
research were carried out at the Stanford Synchrotron Radiation
Laboratory, a national user facility operated by Stanford
University on behalf of the U.S. Department of Energy, Office
of Basic Energy Sciences. The SSRL Structural Molecular
Biology Program is supported by the Department of Energy,
Office of Biological and Environmental Research, and by the
National Institutes of Health, National Center for Research
Resources, Biomedical Technology Program, and the National
Institute of General Medical Sciences.
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Supporting Information Available: Experimental procedures
for compound synthesis, analytical measurements, and enzymatic
assays. The PDB file for the BACE-1/inhibitor 7 complex has been
deposited into the protein data bank PDB (code 2FDP). This
material is available free of charge via the Internet at http://
pubs.acs.org.
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