NGP555
目录号 : GC30887
A γ-secretase modulator
Cas No.:1304630-27-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | SH-SY5Y-APP cells, Tg2576 mixed brain cultures, or C57 mixed brain cultures are treated with various concentrations of NGP555 in triplicate wells, for 18 hours. Media is collected and analyzed for Aβ peptides using triplex ELISA (Aβ38 and Aβ42)[1]. |
Animal experiment: | For CSF studies, Normal Sprague-Dawley male rats (250 to 300 g) are administered NGP555 in 80% PEG orally or vehicle only, n=10/group. Rats are dosed once-daily for a single-dose or 14 days of dosing. After the final dose, cerebrospinal fluid (CSF) samples are either collected at varying time points or a single time point post-last dose. Rats are deeply anesthetized with isoflurane, and CSF is collected from the cisterna magna. Samples are tested for Aβ level. For Y-maze study, transgenic mice (Tg2576 line expressing the APP-Swe mutation) and non-transgenic age-matched littermates (n=a minimum of 12/group) are treated with vehicle, NGP555 (25 mg/kg) once-daily for 30 consecutive days (starting at 5 months of age). At 6 months, mice are assessed on the Y-maze behavior test[1]. |
References: [1]. Kounnas MZ, et al. NGP 555, a γ-Secretase Modulator, Lowers the Amyloid Biomarker, Aβ42, in Cerebrospinal Fluid while Preventing Alzheimer's Disease Cognitive Decline in Rodents. Alzheimers Dement (N Y). 2017 Jan;3(1):65-73. | |
NGP-555 is a modulator of γ-secretase that inhibits APP intracellular signaling domain (AICD) cleavage to amyloid-β (Aβ; IC50s = 531 and 131 nM for Aβ40 and Aβ42, respectively, in HeLa cell membranes).1 It is selective for AICD cleavage to Aβ over E-cadherin and Notch cleavage to their signaling effectors, E-cadherin γ-C-terminal fragment and NICD, respectively, processes also mediated by γ-secretase, when used at a concentration of 30 ?M. Dietary administration of NGP-555 (~50 mg/kg per day) reduces cortical and hippocampal plaque area in the Tg2576 transgenic mouse model of Alzheimer's disease.1 NGP-555 (25 mg/kg per day, p.o.) decreases plasma and brain Aβ40 and Aβ42 levels, as well as increases spontaneous alternations in the Y-maze, indicating prevention of memory deficits, in Tg2576 mice.2
1.Kounnas, M.Z., Danks, A.M., Cheng, S., et al.Modulation of γ-secretase reduces β-amyloid deposition in a transgenic mouse model of Alzheimer's diseaseNeuron67(5)769-780(2010) 2.Kounnas, M.Z., Lane-Donovan, C., Nowakowski, D.W., et al.NGP 555, a γ-secretase modulator, lowers the amyloid biomarker, Aβ42, in cerebrospinal fluid while preventing Alzheimer's disease cognitive decline in rodentsAlzheimers Dement. TRCI3(1)65-73(2017)
| Cas No. | 1304630-27-0 | SDF | |
| Canonical SMILES | CC1=CN(C2=CC=C(C3=CSC(NC4=CC(CC)=C(C)C=C4C)=N3)C=C2F)C=N1 | ||
| 分子式 | C23H23FN4S | 分子量 | 406.52 |
| 溶解度 | DMSO : 42.9 mg/mL (105.53 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4599 mL | 12.2995 mL | 24.599 mL |
| 5 mM | 0.492 mL | 2.4599 mL | 4.9198 mL |
| 10 mM | 0.246 mL | 1.23 mL | 2.4599 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention
A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.
American Chemical Society - 240th national meeting - chemistry for preventing and combating disease: part 1
The 240th National Meeting of the American Chemical Society, held in Boston, included topics covering new therapeutic research. This conference report highlights selected presentations on negative allosteric modulators of metabotropic glutamate receptor 5 (mGluR5) for the treatment of Parkinson's disease, BACE1 inhibitors and γ-secretase inhibitors for the prevention or treatment of Alzheimer's disease, opioid modulators for the treatment of reward disorders, SGLT2 inhibitors for the treatment of diabetes, backup compounds to the DPP-4 inhibitor sitagliptin (Januvia) for type 2 diabetes, and MCH R1 inhibitors for the treatment of obesity. Investigational drugs discussed include SCH-1359113 and SCH-1682496 (both Merck & Co), NGP-555 (NeuroGenetic Pharmaceuticals), ALKS-33 (Alkermes), dapagliflozin (Bristol-Myers Squibb/AstraZeneca) and GSK-882380 (GlaxoSmithKline).