β-Secretase Inhibitor IV binds to the active site of BACE-1 and effectively blocks its proteolytic activity (IC₅₀=15nM)[1-2]. β-Secretase Inhibitor IV reduces the production of amyloid-β peptide by inhibiting the β-secretase cleavage site of amyloid precursor protein. β-Secretase Inhibitor IV can be used in research related to neurodegenerative diseases such as Alzheimer's disease[3-4].
In vitro, β-Secretase Inhibitor IV (0.36μM) was incubated with mouse Neuro2a (N2a) cells for 24 hours, which inhibited the secretion of amyloid-β peptide Aβ40[5]. β-Secretase Inhibitor IV (29nM) was incubated with HEK293FT cells for 6 hours. β-Secretase Inhibitor IV significantly inhibited intracellular BACE-1 activity[6].
In vivo, a single intraperitoneal injection of β-Secretase Inhibitor IV (8mg/kg) was administered to Tg2576 transgenic mice expressing amyloid precursor protein (APP). After 4 hours, β-Secretase Inhibitor IV significantly reduced plasma Aβ40 levels[7].
References:
[1] Z Pietrak BL, Crouthamel MC, Tugusheva K, et al. Biochemical and cell-based assays for characterization of BACE-1 inhibitors. Anal Biochem. 2005 Jul 1;342(1):144-51.
[2] Cheng XR, Zhou JW, Zhou Y, et al. The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a β-secretase inhibitor. Bioorg Med Chem Lett. 2012 Feb 1;22(3):1408-14.
[3] Zhu YP, Xiao K, Yu HP, et al. Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids. Acta Pharmacol Sin. 2009 Feb;30(2):259-69.
[4] Nordeman P, Estrada S, Odell LR, et al. (11)C-Labeling of a potent hydroxyethylamine BACE-1 inhibitor and evaluation in vitro and in vivo. Nucl Med Biol. 2014 Jul;41(6):536-43.
[5] Garino C, Tomita T, Pietrancosta N, et al. Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human beta-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays. J Med Chem. 2006 Jul 13;49(14):4275-85.
[6] Choi SJ, Cho JH, Im I, et al. Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors. Eur J Med Chem. 2010 Jun;45(6):2578-90.
[7] Ghosh AK, Kumaragurubaran N, Hong L, et al. Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem. 2007 May 17;50(10):2399-407.
β-Secretase Inhibitor IV可与BACE-1活性位点结合并有效阻断其蛋白水解活性（IC₅₀=15nM）[1-2]。β-Secretase Inhibitor IV通过抑制淀粉样前体蛋白的β-分泌酶裂解位点来减少淀粉样β肽的产生。β-Secretase Inhibitor IV可用于阿尔茨海默病等神经退行性疾病的相关研究[3-4]。
在体外，β-Secretase Inhibitor IV（0.36μM）孵育小鼠Neuro2a（N2a）细胞24小时，可抑制细胞分泌的淀粉样β肽Aβ40[5]。β-Secretase Inhibitor IV（29nM）孵育HEK293FT细胞6小时。β-Secretase Inhibitor IV显著抑制胞内BACE-1活性[6]。
在体内，β-Secretase Inhibitor IV（8mg/kg）单次腹腔注射于表达淀粉样前体蛋白（APP）的Tg2576转基因小鼠模型。在4小时后，β-Secretase Inhibitor IV可显著降低血浆中的Aβ40水平[7]。