N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated γ-secretase

N-Sulfonylated and N-alkylated carbazolyloxyacetic acids were investigated for the inhibition and modulation of the Alzheimer’s disease associated γ-secretase. The introduction of a lipophilic substituent, which may vary from arylsulfone to alkyl, turned 2-carbazolyloxyacetic acids into potent γ-secretase modulators. This resulted in the selective reduction of Aβ42 and an increase of the less aggregatory Aβ38 fragment by several compounds (e.g., 7d and 8c). Introduction of an electron donating group at position 6 and 8 of N-substituted carbazolyloxyacetic acids either decreased the activity or inversed modulation. The most active compounds displayed activity on amyloid precursor protein (APP) overexpressing cell lines in the low micromolar range and little or no effect on the γ-secretase cleavage at the ε-site.