MEDI 237 |
| Alzheimer's Disease (AD) is a progressive, degenerative disease of the human brain and inflicts mainly older people. The initial symptoms include memory loss, impaired judgment, and disorientation. The progression of AD leads to impairment of the brain and eventually death. Although the cause of AD is still unclear, increasing evidence implicates the amyloid b-peptide (Ab, 39–43 residues) in the neurodegenerative pathogenesis. Ab is formed by the sequential cleavage of the cell membrane anchored b-amyloid precursor protein (APP) by two proteases, known as b- and g-secretases. The Ab peptide is neurotoxic and the principal component of the neuritic plaque found in the brains of AD patients. Inhibition of secretases responsible for Ab formation may stop or slow AD progression by preventing its production. The design and synthesis of highly potent, selective and orally active inhibitors of b-secretase (BACE1) was based on the HTS hit WY-24454 (IC50 = 40 uM). Our SAR design strategy supported by X-ray structures of BACE1 co-crystallized with various ligands, and molecular modeling studies. This approach enabled us to rapidly explore the rather large ligand-binding pocket of BACE1 and identify key protein/ligand interactions that produced structurally diverse, and highly potent (IC50 ~10 nM) BACE1 inhibitors. Key ligand-protein interactions were recognized to produce highly selective compounds against other aspartyl protease proteins, such as BACE2, and Cathepsin D. Several compounds have demonstrated high potency in cell-based assays, and were also orally efficacious in vivo, near normalizing plasma Ab levels. These orally active and selective BACE1 inhibitors will contribute toward the understanding of APP processing, as well as the development of disease-modifying AD therapeutics. |
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General Oral Session
1:30 PM-4:50 PM, Tuesday, August 21, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |