| Description | Semagacestat (LY450139) (LY450139) is a γ-secretase blocker for Aβ42/Aβ40/Aβ38 (IC50: 10.9/12.1/12.0 nM) and also inhibits Notch signaling (IC50: 14.1 nM). |
| In vitro | Semagacestat通过降低从稳定过表达人类野生型APP的H4人类胶质瘤细胞中向培养基中分泌的Aβ42、Aβ40和Aβ38，其IC50分别为10.9 nM、12.1 nM和12.0 nM，同时不影响细胞活性。此外，Semagacestat能够增加细胞裂解液中的β-CTF，其ECmax为16.0 nM，且在高浓度时该增加效应会出人意料地减弱。Semagacestat抑制Notch信号传导，IC50为14.1 nM，对Notch的选择性极小，Notch IC50/Aβ42 IC50仅为1.3。[1] 对于表达内源性小鼠APP的小鼠CTX，Semagacestat导致Aβ40在介质中浓度依赖性下降，IC50为111 nM，但小鼠Aβ42的形成量大约是Aβ40的12倍，这与野生型小鼠神经元的数据相符。[2] |
| In vivo | 经口给予5.5个月大的APP转基因Tg2576小鼠Semagacestat（1 mg/kg），能显著改善使用Y迷宫任务测量的空间工作记忆缺陷，但在连续服用8天后，该效果消失。LY450139在剂量为10 mg/kg时能使海马Aβ42和Aβ40水平分别降低22-23%，在30 mg/kg时降低36-41%，并在0.3-10 mg/kg剂量依赖性增加β-CTF，但不抑制大脑中其他γ-分泌酶底物（如Notch, N-钙黏蛋白或EphA4）的处理。然而，LY450139在野生型小鼠和3月龄Tg2576小鼠中损害了正常的认知功能，未能在Y迷宫测试中恢复认知缺陷。[1] |
| Cell experiments | Cells are incubated with Semagacestat for 24 hours. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) following incubation with 0.5 mg/mL MTT for 60 minutes. For the detection of sAPP species, cells are lysed and analysed by western blotting.(Only for Reference) |
| Target activity | γ-secretase (Aβ40):12.1 nM, γ-secretase (Aβ38):12.0 nM, γ-secretase (Aβ42):10.9 nM |
| Synonyms | LY450139, 塞美司他 |
| molecular weight | 361.44 |
| Molecular formula | C19H27N3O4 |
| CAS | 425386-60-3 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | H2O: < 1 mg/mL (insoluble or slightly soluble) DMSO: 67 mg/mL (185.4 mM) Ethanol: 39 mg/mL (107.9 mM) |
| References | 1. Mitani Y, et al. J Neurosci, 2012, 32(6), 2037-2050. 2. Elvang AB, et al. J Neurochem, 2009, 110(5), 1377-1387. |