Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).

We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme β-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.