BACE1, also known as β-secretase, is an aspartyl protease that controls the formation of amyloid β, a peptide crucial for the pathogenesis of Alzheimer’s disease. LY2886721 is a potent BACE1 inhibitor with an IC50 value of 20.3±10.1nM. It also exhibits inhibitory activity against human BACE2, a closely related aspartyl protease, with an IC50 value of 10.2±4.8nM. Overnight treatment of HEK293Swe cells with increasing concentrations of LY2886721 led to a dose-dependent decrease in the amount of amyloid β secreted into the medium. The EC50 values for the inhibition of amyloid β1-40 and amyloid β1-42 were 18.5nM and 19.7nM, respectively. Overnight exposure of mouse neuronal cultures with increasing concentrations of LY2886721 also dose-dependently decreased the production of amyloid β with an EC50 value of ~10nM. In PDAPP mice, oral administration of LY2886721 at 3, 10, and 30mg/kg significantly reduced hippocampal and cortical levels of amyloid β1-x compared with the vehicle-treated group. Mice administered with LY2886721 showed reduced brain parenchymal levels of C99 (at 10 and 30mg/kg) and sAPPβ (at 3, 10, and 30mg/kg) compared to the control group.[1]
作用机制
LY2886721 is a BACE1 active site inhibitor with selectivity against cathepsin D, pepsin, and renin.[1]
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