MEDI 236 |
| Alzheimer's Disease (AD) is a progressive, degenerative disease of the brain and most common form of dementia. Increasing evidence implicates the amyloid b-peptide (Ab, 39–43 residues) in the neurodegenerative pathogenesis. 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, and selective inhibitors of b-secretase (BACE1) was based on the initial hit 2-amino-3-methyl-5,5-diphenyl-3,5-dihydro-4H-imidazol-4-one (IC50 = 3 uM). Our SAR design strategy supported by molecular modeling studies and X-ray structures of BACE1 co-crystallized with various ligands. This approach enabled us to identify distinct areas within the various sub-sites of the rather large ligand-binding pocket of BACE1 and design pyridine containing 2-amino-3,5-dihydro-4H-imidazol-4-ones as highly potent (IC50 ~10 nM) and selective (>300x vs BACE2; >1000x vs Cathepsin D) BACE1 inhibitors. Key residue/size differences at the S2' sub-site between the BACE1 and BACE2 & Cathepsin D were recognized and have contributed to the selectivity of the compounds. We were able to direct substitutions toward the FLAP region of the binding pocket, as well as deep into S2' region and markedly improve the selectivity of the compounds. Several compounds have demonstrated high potency in ELISA cell-based assays as well. These potent 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 |