Product Overview
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-β peptide (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. In SH-SY5Y cells, LY2811376 reduced Aβ 1-40 and Aβ 1-42 secreted to the cell medium while increased the level of Aβ 5-40. In the APPV717F mouse, LY2811376 significantly reduced Aβ, as well as sAPP and C99, the cleavage products of APP by BACE1.In a healthy population (n =18), LY2811376 (30 mg, 90 mg) increased Aβ 5-40 and Aβ 5-X in a dose-dependant way, while Aβ 1-34 reduced in a same way. These results suggested that LY2811376 inhibited N-terminally truncated Aβ peptides in a BACE1-independent pathway.
Chemical Name
(4S)-4-(2,4-difluoro-5-pyrimidin-5-ylphenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine
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