Alzheimer's disease (AD) is the most common neurodegenerative disease, representing one of the largest unmet medical needs in neuroscience today.  A key factor in AD pathogenesis is the accumulation of beta-amyloid peptides (Ab) in the brain, where formation of these peptides is initiated via proteolytic cleavage of amyloid precursor protein (APP) by the aspartyl protease BACE1 (b-Secretase).  Although significant efforts have focused on the inhibition of BACE1 as a possible disease-modifying therapy for AD, identifying orally available, CNS-penetrant BACE1 inhibitors has proven particularly challenging.  We report the structure-based optimization of amino-heterocyclic xanthene BACE inhibitors.  The use of extensive X-ray cocrystallographic information combined with effective control of physiochemical properties to maximize CNS-exposure led to the identification of potent, selective, and orally available inhibitors which show robust reduction of brain (Ab) in preclinical species.

Lead optimization of aminoheterocyclic xanthenes: Identification of potent, CNS-penetrant BACE inhibitors for the treatment of Alzheimer's disease

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.