Alzheimer’s disease is characterized by the early deposition of aggregated peptides (Ab<sub>40,42</sub>) and the subsequent formation of amyloid plaques , neurofibrillary tangles and dystrophic neurites in brain. The aggregated peptides are formed by sequential enzymatic cleavage of amyloid precursor protein (APP), initially by beta secretase (BACE) and subsequently by gamma secretase. Inhibition of either of these enzymes thus forms a potential therapeutic opportunity for protecting the brain from the Ab peptide. Our target, BACE 1 is a membrane bound aspartic acid protease found mainly in brain. Our effort has been focused on the development of SAR in three regions of an inhibitor molecule from the thioamidine class. This presentation will delineate the chemistry strategy we used to investigate substituents of the fused thioamidine series, especially substituents that occupy P2’, P1 and P3 binding pockets of BACE1. The route is stereoselective with the creation of up to 4 stereocenters through the use of a nitrile oxide 3+2 cycloaddition and a stereoselective aryl anion addition.

SAR enablement of multifunctional BACE templates: Thioamidines

249th National Meeting (2015)

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