A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an amide chemotype that engages a key residue (GLY230) in the BACE1 binding site. Although the amide subunit affords excellent potency, it simultaneously imparts significantly diminished brain availability and contains a structural alert. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series required careful examination and tuning of the pKa of the linker to align potency with minimized efflux. This optimization revealed a convergence of SAR between BACE1 and CYP 2D6 for this series that required a structure-driven design strategy to obviate the 2D6 liability and deliver a selective BACE1 inhibitor that exhibits robust in vivo efficacy.

Beta-secretase (BACE1) inhibitors for Alzheimer’s disease

251st National Meeting (2016)

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