LY2811376 is a non-peptidic inhibitor of BACE1.Beta-secretase 1 (BACE1) is an aspartic-acid protease that cleaves the amyloid precursor protein (APP) into amyloid-βpeptide (Aβ), which plays a critical role in Alzheimer’s disease (AD).In recombinant enzyme assays, LY2811376 inhibited hBACE1 with IC50 values of 249 nM and 239 nM against a larger chimeric protein substrate and a small synthetic peptide, respectively. In a human embryonic kidney cell line overexpressed APP, LY2811376 decreased Aβ secretion with EC50 value of 300 nM in a concentration-dependant way [1]. In SH-SY5Y cells, LY2811376 reduced Aβ1-40 and Aβ1-42 secreted to the cell medium while increased the level of Aβ5-40 [2].In the APPV717F mouse, LY2811376 significantly reduced Aβ, as well as sAPP and C99, the cleavage products of APP by BACE1 [1]. In a healthy population (n =18), LY2811376 (30 mg, 90 mg) increased Aβ5-40 and Aβ5-X in a dose-dependant way, while Aβ1-34 reduced in a same way. These results suggested that LY2811376 inhibited N-terminally truncated Aβ peptides in a BACE1-independent pathway [2].References:[1]. May PC, Dean RA, Lowe SL, et al. Robust Central Reduction of Amyloid- in Humans with anOrally Available, Non-Peptidic -Secretase Inhibitor. J Neurosci, 2011, 31(46): 16507-16516. [2]. Portelius E, Dean RA, Andreasson U, et al. β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage. Alzheimers Res Ther, 2014, 6(5-8): 75.