An exploration of the SAR of the side chain of a novel tricyclic series of 纬-secretase inhibitors led to the identification of compound (鈭?-
16 (SCH 900229), which is a potent and PS1 selective inhibitor of 纬-secretase (A尾40 IC
50 = 1.3 nM). Compound (鈭?-
16 demonstrated excellent lowering of A尾 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鈥檚 disease.
Keywords:
纬-Secretase inhibitor; Alzheimer鈥檚 disease; amyloid; notch; clinical candidate