Semagacestat (LY450139)

Orally administered once daily

Murine cortical neurons and cerebellar granule cells

Phase III study has been completed in evaluating the effect of LY450139 on the progression of Alzheimer's disease as compared with placebo.

Semagacestat (LY450139) is a gamma-secretase blocker for Abeta42, Abeta40 and Abeta38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively. Semagacestat also inhibits Notch signaling with IC50 of 14.1 nM.

Semagacestat is the best documented gamma-secretase inhibitor that has reached clinical testing.

10.9 nM, 10.9 nM, 10.9 nM, 10.9 nM, 10.9 nM, 10.9 nM

Oral administration of Semagacestat (1 mg/kg) to 5.5-month old APP-transgenic Tg2576 mice significantly ameliorates memory deficits on spatial working memory using the Y-maze task, which disappears after 8 days subchronic dosing. LY450139 decreases hippocampal levels of both Abeta42 and Abeta40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction) and increases beta-CTF at 0.3-10 mg/kg in a dose dependent manner with no inhibition on the processing of other gamma-secretase substrates, such as Notch, N-cadherin or EphA4, in the brain, but impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice failing to restore cognitive deficits in the Y-maze test. [1]

Cellular APP processing assay and Notch signaling assay, H4 human glioma cells stably overexpressing human wild-type APP695 are treated with Semagacestat at various concentrations for 24 hours. Levels of Abeta42, Abeta40, and Abeta38 in the media are measured using separate ELISA kits. The expression vector of the constitutively active form of Notch (NotchdeltaE), encoding bases 1-60 and 5193-6657 of the human Notch1 coding region (NM_017617), is constructed into a pcDNA3.1 vector with a sequence modification from mouse to human. Notch signaling activity is evaluated using Cignal RBP-Jk Reporter Assay kit. RBP-Jk protein [CSL/CBF1/Su(H)/Lag1] is a transcription factor activated with Notch intracellular domain produced by gamma-secretase. H4 cells are transiently transfected with the human NotchdeltaE expression vector and the RBP-Jk-responsive luciferase construct using Lipofectamine 2000, and then exposed to various concentrations of Semagacestat for 16 hours. Notch signaling is measured based on luciferase activity in the cell lysate using the Dual-Glo Luciferase Assay System.

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DMSO 72 mg/mL, Water <1 mg/mL, Ethanol 43 mg/mL