Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (−)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (−)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer’s disease.