We describe the discovery and optimization of tertiarycarbinamine derived inhibitors of the enzyme G SRC="/images/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-secretase (BACE-1).These novel non-transition-state-derived ligands incorporate a singleprimary amine to interact with the catalytic aspartates of the targetenzyme. Optimization of this series provided inhibitors with intrinsicand functional potency comparable to evolved transition state isosterederived inhibitors of BACE-1.