Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.

A growing subset of β-secretase ( BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an anilide chemotypethat engages a key residue (Gly230) in the BACE1binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motifof prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potencyand improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions(DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1inhibitor.