BPN-15606
目录号 : GC39566
BPN-15606 是一种高效的口服活性 γ-secretase 调节剂 (GSM)，可减弱 SHSY5Y 神经母细胞瘤细胞产生 Aβ42 和 Aβ40 的作用，IC50 值分别为 7 nM 和 17 nM。BPN-15606 显着降低大鼠和小鼠中枢神经系统中的 Aβ42 和 Aβ40 水平。BPN-15606 具有良好的 PK/PD 特性，包括生物利用度，半衰期和清除率。
Cas No.:1914989-49-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BPN-15606 is a highly potent, orally active γ-secretase modulator (GSM), attenuates the production of Aβ42 and Aβ40 by SHSY5Y neuroblastoma cells with IC50 values of 7 nM and 17nM, respectively. BPN-15606 significantly lowers Aβ42 and Aβ40 levels in the central nervous system of rats and mice. BPN-15606 has acceptable PK/PD properties, including bioavailability, half-life, and clearance[1].
[1]. Wagner SL, et al. Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606. J Pharmacol Exp Ther. 2017 Jul;362(1):31-44.
| Cas No. | 1914989-49-3 | SDF | |
| Canonical SMILES | CC1=CC(C2=NC(OC)=C(N3C=C(C)N=C3)C=C2)=NN=C1N[C@H](C4=CC=C(F)C=C4)C | ||
| 分子式 | C23H23FN6O | 分子量 | 418.47 |
| 溶解度 | DMSO: 100 mg/mL (238.97 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 | 2.3897 mL | 11.9483 mL | 23.8966 mL |
| 5 mM | 0.4779 mL | 2.3897 mL | 4.7793 mL |
| 10 mM | 0.239 mL | 1.1948 mL | 2.3897 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。
The GSM BPN-15606 as a Potential Candidate for Preventative Therapy in Alzheimer's Disease
J Alzheimers Dis 2020;73(4):1541-1554.PMID:31958080DOI:10.3233/JAD-190442.
Background: In the amyloid hypothesis of Alzheimer's disease (AD), the dysregulation of amyloid-β protein (Aβ) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aβ production have been found ineffective or having significant side effects. Objective: To test whether a γ-secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. Methods: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points. Results: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed. Conclusion: BPN-15606 appears efficacious when administered prior to significant pathology.
Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606
J Pharmacol Exp Ther 2017 Jul;362(1):31-44.PMID:28416568DOI:10.1124/jpet.117.240861.
Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials.
Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease
Alzheimers Dement 2022 Nov;18(11):2117-2130.PMID:35084109DOI:10.1002/alz.12553.
While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi-omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early-onset Alzheimer's (EOFAD) disease patient lineage PSEN1A246E iPSC-derived neurons, we performed RNA-seq to characterize AD-associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN-15606. We demonstrate that drug treatment partially restores the neuronal state while concomitantly inhibiting cell cycle re-entry and dedifferentiation endotypes to different degrees depending on the mechanism of gamma secretase engagement. Our endotype-centric screening approach offers a new paradigm by which candidate AD therapeutics can be evaluated for their overall ability to reverse disease endotypes.