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.

Graphical abstractThe synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described.Figure optionsDownload full-size imageDownload as PowerPoint slide