Alzheimer's disease (AD), a common form of dementia characterized by memory loss, cognitive impairment, and ultimately death, is a serious unmet medical need costing hundreds of billions of dollars annually. The pathogenesis of Alzheimer's is believed to involve the accumulation and aggregation of Ab peptide fragments to form insoluble plaques in the brain. The enzyme BACE1 is responsible for initiating the formation of Ab fragments; consequently, inhibition of BACE1 in the brain has emerged as an attractive target for treatment of AD within the pharmaceutical industry.During our efforts to develop a series of aminooxazoline xanthenes as potent and selective BACE1 inhibitors, we utilized crystallographic data to develop a series of 4-azaxanthenes with increased BACE1 potency and reduced off-target hERG activity.  In order to further optimize BACE1 potency while maintaining the high permeability and low Pgp-mediated efflux required for adequate CNS exposure, extensive examination of the P2' and P3 substituents was conducted. This work identified several modifications that led to increased BACE1 potency, reduced hERG activity, and improved permeability and Pgp-efflux. Additionally, several novel heterocyclic warheads were designed as alternatives to the aminooxazoline moiety to modify the physiochemical profile of our inhibitors. These efforts resulted in potent, selective BACE1 inhibitors with low hERG activity, good CNS penetration, and robust reduction of brain A� levels in a preclinical rodent model.

Design and optimization of heterocyclic 4-azaxanthenes as potent and selective inhibitors of BACE1 for the treatment of Alzheimer's disease

248th National Meeting (2014)

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