Semagacestat

A potent γ-secretase inhibitor that inhibits β-amyloid Aβ42, Aβ38 and Aβ40 with IC50 of 10.9, 12 and 12.1 nM, respectively; reduces the secretion of Aβ42, Aβ40, and Aβ38 in cells and increases β-CTF in cell lysates, also inhibits Notch signaling with IC50 of 14.1 nM; increases intracellular byproduct peptides, produced along with Aβ through serial γ-cleavage of βAPP, as well as intracellular long Aβ species, in cell-based and in vivo studies of AD model mice; a pseudo-inhibitor of γ-secretase.Alzheimer's Disease Phase 3 Discontinued (In Vitro) :Semagacestat (LY450139) reduces the secretion of Aβ42, Aβ40, and Aβ38 in 96-well-cultured media and increases β-CTF in cell lysates as expected, although this increase is unexpectedly attenuated at high concentrations.In cortical neurons (CTX), Semagacestat (LY450139) causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 value 111 nM for Semagacestat. Semagacestat causes a concentration-dependent decrease in Aβ40 and Aβ42 secreted into the medium with an IC50 value of 126 and 130 nM, respectively.Semagacestat (3 Μm; for 4 days) exhibits no significant cell toxicity in Huh7 cells.