The proteolytic cleavage of amyloid precursor protein (APP) to generate toxic A� fragments occurs via a sequence that is initiated by the aspartyl protease BACE1.  It has been proposed that this event plays an early and critical event in the pathogenesis of Alzheimer's disease (AD).  BACE1 knockout mice developed normally and displayed no profound phenotype, suggesting BACE inhibition as a disease modifying therapy for the treatment of AD.   As  a membrane-bound aspartyl protease highly expressed in the central nervous system, the site of action makes effective inhibition of BACE1 in vivo a substantial challenge. This poster will describe our structure- and property-based approach in discovering novel aminooxazoline xanthenes as potent BACE inhibitors. These compounds demonstrate good selectivity against other aspartyl proteases and are orally available. Special emphasis was placed on modulating physiochemical properties to maximize CNS penetration. A set of potent BACE1 inhibitors which demonstrate robust efficacy in a rat pharmacodynamic model will be presented.

Discovery of aminooxazoline xanthenes as potent CNS penetrable BACE inhibitors

244th National Meeting (2012)

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