NSAID-derived γ-secretase modulators. Part III: Membrane anchoring

The synthesis and activity data of N-substituted carbazole- and O-substituted fenofibrate-derived γ-secretase modulators are presented. Out of 19 screened compounds, seven exhibited promising activity against Aβ42 secretion at a low micromolar level. We suggest that the γ-secretase modulators interact with lys624 at the membrane interface and that the lipophilic substituent anchors the compound in the membrane.