A major pathophysiology of Alzheimer's disease (AD) is the presence of amyloid plaques which are primarily composed of the A� peptide.  The formation of the A� peptide is the result of sequential enzymatic cleavage of the Amyloid Precursor Protein (APP) by �-secretase (BACE) and subsequently by ?-secretase.  Small molecule BACE1 inhibitors would be expected to prevent the generation of the A� peptides and consequently reduce the detrimental effects of A� toxicity and the formation of amyloid plaques in the brain. We will describe the identification and optimization of a novel series of spirocyclic lactam BACE-1 inhibitors that bind to the catalytic aspartic acids via water mediated hydrogen bond.  A strategy to align a set of physicochemical properties, CNS penetration, and selectivity into a single molecule led to the discovery of PF-05297909.  The efficacy of PF-05297909 to decrease amyloidogenic peptides in multiple species and in-vivo paradigms provided rationale to advance the compound into human following a single dose exploratory IND study.

Spirocyclic lactams as BACE-1 inhibitors for the treatment of Alzheimer's disease

246th National Meeting (2013)

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