Alzheimer's Disease (AD) is a progressive, degenerative disease of the brain and most common form of dementia. Increasing evidence implicates the amyloid beta-peptide (beta-amyloid, 39�43 residues) in the neurodegenerative pathogenesis. Beta-amyloid is produced in vivo through proteolytic cleavage of the membrane-bound beta-amyloid precursor protein (APP) by beta- and gamma-secretases sequentially. The beta-amyloid peptide is neurotoxic and the principal component of the neuritic plaque found in the brains of AD patients. Inhibition of secretases responsible for beta-amyloid formation may stop or slow AD progression by preventing its production. The design and synthesis of highly potent and selective inhibitors of beta-secretase (BACE1) was based on the HTS hit W-1 (IC50 = 40 mM). The initial aminohydantoins beta-secretase inhibitors, exemplified by W-2 (IC50 = 10 nM), were potent and selective, but demonstrated only weak to moderate brain permeability. As a result, the in vivo efficacy of these inhibitors was very modest. Two major issues have impacted the poor pharmacokinetic properties of theses compounds; the high topological polar surface area, and high susceptibility for the P-glycoprotein transporter protein. In order to overcome these issues, we have identified the areas that have contributed to poor brain permeability and synthesized new aminohydantoins with superior permeation properties. Modification of the P3 side chain of W-2, and optimization of the S2' pocket ligand-protein interactions have led to compounds with lower TPSA, decreased affinity for P-glycoprotein and superior pharmacokinetic properties. Our SAR design strategy supported by X-ray structures of BACE1 co-crystallized with various ligands, molecular modeling studies, and in silico methods. Several compounds have demonstrated excellent activity in the cell-based assay (ELISA; EC50 ~ 10 nM), and were orally efficacious in vivo, near normalizing plasma beta-amyloid and significantly reducing beta-amyloid and solAPPbeta levels in the brain. Lastly, these compounds reversed the cognitive deficits exhibited by Tg2576 mice, as assessed by compound-mediated increased % freezing vs. vehicle in the contextual fear-conditioning model for hippocampal-mediated memory. These new orally active BACE1 inhibitors will contribute toward the understanding of APP processing, as well as the development of disease-modifying AD therapeutics.

New aminohydantoins as BACE1 inhibitors

240th National Meeting (2010)

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