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 gamma-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PSI selective inhibitor of gamma-secretase (A beta 40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of A beta 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.