Abstract
Highly potent BACE-1 protease inhibitors have been developed from an inhibitors containing a hydroxyethylene (HE) core displaying aryloxymethyl or benzyloxymethyl P1 side chain and a methoxy P1' side chain. The target molecules were synthesized in good overall yields from chiral carbohydrate starting materials. The inhibitors show high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnishes BACE-1 K(i) << 1 nM and displays >1000-fold selectivity over cathepsin D.
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