| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1365879 | Bioorganic & Medicinal Chemistry Letters | 2007 | 4 Pages |
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.
Graphical abstractTO-901317 analogue derivatives, where the hexafluorocarbinol moiety was replaced by an oxyacetic acid functionality, switch the mode of action from an inverse modulation to normal modulation of γ-secretase. As anticipated, compound 9 was found to be an effective modulator of γ-secretase and displayed activity at low micromolar concentration.Figure optionsDownload full-size imageDownload as PowerPoint slide
