LY2811376

A potent, orally available non-peptidic β-secretase (BACE1) inhibitor with IC50 of 239 nM in enzyme assays; demonstrates ~10-fold selectivity over BACE2, and >50-fold over aspartyl proteases cathepsin D, pepsin, or renin; produces profound Aβ-lowering effects in vivo.Alzheimer's Disease Phase 1 Discontinued (In Vitro) :In an APP-overexpressing human embryonic kidney cell line, LY2811376 treatment yields a concentration-dependent decrease in Aβ secretion with a half-maximal effective concentration (EC50) of appr 300 nM. LY2811376 treatment of primary neuronal cultures of PDAPP transgenic mouse produces a concentration-dependent decrease in Aβ secretion with an EC50 of appr 100 nM. LY2811376 has good ADME properties (BACE1 IC50=240 nM, cellular potency IC50=300 nM) and selectivity (BACE2 and cathepsin D selectivity: appr 10- and 65-fold, respectively) . LY2811376 reduces the Aβ40 levels in cortex and plasma without change of health and weight in a dose-dependent manner. (In Vivo) :LY2811376 (10, 30, and 100 mg/kg, p.o.) results in dose-dependent, significant reductions in Aβ as well as sAPPβ and C99, the proximal cleavage products of APP proteolysis by BACE1. LY2811376 produces dose-dependent decreases in all APP-related PD markers of BACE1 inhibition in PDAPP mice. Low (30 mg) and high (90 mg) doses of LY2811376 investigated in the CSF sampling study are based on PK and plasma Aβ1-40 PD observed in the SAD study. LY2811376 (30 mg/kg, p.o.) can lead to a 60% decrease in the soluble Aβs in mouse cortex. LY2811376 (100 mg/kg, p.o.) decreases the spine density and formation in mice. LY2811376 (100 mg/kg every 12 hours over 16 days) causes a reduction in the frequency of sEPSC and mEPSC, whereas the effects of LY2811376 on the amplitude of sEPSC fails to reach significance.