Conversion of the LXR-agonist TO-901317—From inverse to normal modulation of γ-secretase by addition of a carboxylic acid and a lipophilic anchor

TO-901317, a LXR agonist, is an inverse modulator of Alzheimer’s disease associated γ-secretase. We synthesized TO-901317 analogous compound but replaced the hexafluorocarbinol moiety by an oxyacetic acid functionality and hypothesized that the replacement would change the mode of action from an inverse modulation to normal modulation of γ-secretase. As anticipated, acid 9 was found to be an effective modulator of γ-secretase and displayed activity at low micromolar concentration. This significant modification can be applied to several inverse γ-secretase modulators. Such modulators may preserve the cleavage of other γ-secretase substrates such as Notch.