Synthesis and evaluation of succinoyl-caprolactam γ-secretase inhibitors

The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of γ-secretase and high potency in cellular assays of Aβ reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.