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A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development.

The aspartyl protease β-secretase, or BACE, hasbeen demonstrated to be a key factor in the proteolytic formationof Aβ-peptide, a major component of plaques in the brains ofAlzheimer’s disease (AD) patients, and inhibition of this enzymehas emerged as a major strategy for pharmacologic intervention inAD. An X-ray-based fragment screen of Pfizer’s proprietaryfragment collection has resulted in the identification of a novelBACE binder featuring spiropyrrolidine framework. Although exhibitingonly weak inhibitory activity against the BACE enzyme, the small compoundwas verified by biophysical and NMR-based methods as a bona fide BACEinhibitor. Subsequent optimization of the lead compound, relying heavilyon structure-based drug design and computational prediction of physiochemicalproperties, resulted in a nearly 1000-fold improvement in potencywhile maintaining ligand efficiency and properties predictive of goodpermeability and low P-gp liability. [ABSTRACT FROM AUTHOR]