Alzheimer's disease (AD) is a progressive neurological disease of the brain that leads to the irreversible loss of neurons and dementia.  The accumulation of the beta-amyloid peptide (Ab) in the brains is a key early initiating event in the pathogenesis of this disorder.  Ab is produced by sequential endoproteolytic cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase.  BACE1 is responsible for the initial cleavage of the APP and is believed to be the rate limiting step in Ab production.  Thus, BACE1 is considered to be a prime therapeutic target for the development of disease-modifying therapies for AD.  There are significant challenges in designing low molecular weight, brain penetrant, and potent BACE1 inhibitors.  We used a fragment-based lead generation approach and identified 2-aminoquinoline as an initial fragment hit that displayed potency in the millimolar range with excellent ligand efficiency.  Structure guided evolution of this fragment using X-ray crystallography expedited the SAR development for potent inhibitors.  Further elaboration on physicochemical properties required for CNS penetration led to potent BACE1 inhibitors that lower CSF Ab levels in rat.

Development of 2-aminoquinolines as potent inhibitors of BACE1

243rd National Meeting (2012)

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