SPI-1865

SPI-1865 is a novel orally bioavailable small molecule gamma-secretase modulator (GSM) discovered by Satori Pharmaceuticals for the potential treatment of Alzheimer's disease. It selectively lowers the amyloidogenic Aβ42 and Aβ38 peptides while largely sparing Aβ40 and total Aβ levels, consistent with modulation of gamma-secretase processivity rather than inhibition of enzyme activity, and shows nanomolar potency in vitro.[2] In multiple rodent models, SPI-1865 is brain-penetrant and produces dose-responsive reductions in brain and plasma Aβ42, with a long half-life and pharmacokinetic/pharmacodynamic relationships supporting once-daily dosing.[1][2] Preclinical-scale synthesis and kilogram-scale API production routes have been described, but the compound has remained at the preclinical development stage for Alzheimer's disease.[9][11]