LY2886721

LY2886721 is a highly potent, selective BACE1 aspartyl protease inhibitor with IC50 of 20.3 and 10.2 nM for BACE1 and BACE2, shows no inhibition against cathepsin D, pepsin, renin, or other aspartyl proteases; produces a concentration-dependent decrease in Aβ1-40 and Aβ1-42 production in HEK293Swe cells (EC50s=10 nM) ; demonstrates robust in vivo amyloid β lowering effect in nonclinical animal models, shows similar potent and persistent amyloid β lowering was observed in plasma and lumbar in clinical trials.Alzheimer Disease Phase 2 Discontinued (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 Aβ1-40 and Aβ1-42 are essentially identical, 18.5 and 19.7 nM, respectively.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 Aβ1-40 and Aβ1-42 are comparable in PDAPP neuronal cultures at ~10 nM. (In Vivo) :LY2886721 (3-30 mg/kg; oral administration; PDAPP mice) treatment significantly reduces the hippocampal and cortical levels of Aβ1-x. LY2886721 treatment results in significant reduction of brain parenchymal levels of C99 and sAPPβ.