Design and synthesis of tricyclic sulfones as γ-secretase inhibitors with greatly reduced Notch toxicity

A novel series of tricyclic γ-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous γ-secretase inhibitors.

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