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[1]. LY2811376 (30 mg/kg, p.o.) can lead to a 60% decrease in the soluble Aβs in mouse cortex[2]. 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[4].
