Design and synthesis of benzoazepinone-derived cyclic malonamides and aminoamides as potent γ-secretase inhibitors

We report the synthesis of benzoazepine-derived cyclic malonamides (2) and aminoamides (3) as γ-secretase inhibitors for the potential treatment of Alzheimer’s disease. The in vitro structure–activity relationships of 2 and 3 along with dog pharmacokinetic results are described.

Graphical abstractCompounds such as 2h (APP IC50 = 5.8 nM) and 3l (APP IC50 = 4.2 nM) are potent γ-secretase inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide