Central deposition of amyloid-� peptide (A�) is critical in Alzheimer's disease (AD) pathogenesis.  A� generation is initiated when �-secretase (BACE1) cleaves the amyloid precursor protein.  For more than a decade BACE1 has been a prime target for designing drugs to prevent or treat AD.  However, development of such agents has turned out to be extremely challenging with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access.  Using a fragment-based chemistry strategy, we have generated LY2811376, the first orally available non-peptidic BACE1 inhibitor that produces profound A�-lowering effects in animals, and importantly, translates into strong and long-lasting A� reduction in human CNS.  Our studies with LY2811376 demonstrate that BACE1 is a tractable small-molecule target with promise for the development of AD therapeutics.

Central inhibition of Alzheimer's beta-secretase in humans:  Proof of concept with LY2811376

243rd National Meeting (2012)

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