LY2886721

LY2886721 is a potent, selective and orally active beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor with an IC₅₀ of 20.3 nM for recombinant human BACE1. LY2886721 is selectivity against cathepsin D, pepsin, and renin, but lacking selectivity against BACE2 (IC₅₀ of 10.2 nM). LY2886721 can across blood-brain barrier and has the potential for Alzheimer's disease treatment^[1]. IC50 & Target: IC50: 20.3 nM (Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)); 10.2 nM (BACE2)^[1] In Vitro: Overnight exposure of HEK293Swe cells to increasing concentrations of LY2886721 shows a concentration-dependent decrease in the amount of Aβ secreted into the condition medium. Consistent with a mechanism of BACE inhibition, the EC₅₀s for inhibition of Aβ_1-40 and Aβ_1-42 are essentially identical, 18.5 and 19.7 nM, respectively^[1].
Overnight exposure of PDAPP neuronal cultures to an increasing concentration of LY2886721 produces a concentration-dependent decrease in Aβ production. As observed in HEK293Swe cells, the EC₅₀s for inhibition of Aβ_1-40 and Aβ_1-42 are comparable in PDAPP neuronal cultures at ∼10 nM^[1]. In Vivo: LY2886721 (3-30 mg/kg; oral administration; PDAPP mice) treatment significantly reduces the hippocampal and cortical levels of Aβ_1-x. LY2886721 treatment results in significant reduction of brain parenchymal levels of C99 and sAPPβ^[1].