YQ128
目录号 : GC39311
An NLRP3 inflammasome inhibitor
Cas No.:2454246-18-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
YQ-128 is an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome (IC50 = 0.3 ?M).1 It inhibits LPS- and ATP-induced IL-1β release from isolated mouse peritoneal macrophages (IC50 = 1.59 ?M). YQ-128 (10 mg/kg) inhibits LPS-induced IL-1β production in wild-type but not Nlrp3-/- mice.
1.Jiang, Y., He, L., Green, J., et al.Discovery of second-generation NLRP3 inflammasome inhibitors: Design, synthesis, and biological characterizationJ. Med. Chem.62(21)9718-9731(2019)
| Cas No. | 2454246-18-3 | SDF | |
| Canonical SMILES | O=S(C1=CC=C(CCN(CC2=C(C=CC(Cl)=C2)OCCC)C(CC3=CSC=C3)=O)C=C1)(NCC#C)=O | ||
| 分子式 | C27H29ClN2O4S2 | 分子量 | 545.11 |
| 溶解度 | DMSO: 250 mg/mL (458.62 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 | 1.8345 mL | 9.1725 mL | 18.3449 mL |
| 5 mM | 0.3669 mL | 1.8345 mL | 3.669 mL |
| 10 mM | 0.1834 mL | 0.9172 mL | 1.8345 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。
Development of sulfonamide-based NLRP3 inhibitors: Further modifications and optimization through structure-activity relationship studies
Eur J Med Chem 2022 Aug 5;238:114468.PMID:35635948DOI:10.1016/j.ejmech.2022.114468.
NLRP3 inflammasome dysregulation has been observed in many human diseases including neurodegenerative disorders. Thus, development of small molecule inhibitors targeting this protein complex represents a promising strategy to achieve disease intervention. In our continuing efforts to develop NLRP3 inhibitors, a recently identified lead inhibitor, YQ128, was further modified and optimized. The structure-activity relationship studies of this lead compound suggested its flexibility for structural modifications while the sulfonamide and benzyl moiety demonstrated being important for selectivity. Additionally, the systematic SAR studies also provided insights for designing NLRC4 and AIM2 inflammasome inhibitors. A new lead inhibitor, 19, was identified with improved potency (IC50: 0.12 ± 0.01 μM) and binding affinity (KD: 84 nM). Further characterization of this lead compound using wild type and nlrp3-/- mice confirmed its in vivo selective target engagement. PET studies using a radiotracer based on the structure of 19 also demonstrated its improved brain penetration compared to previous lead compounds. These results strongly encourage further testing of 19 in disease models.
Discovery of Second-Generation NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization
J Med Chem 2019 Nov 14;62(21):9718-9731.PMID:31626545DOI:10.1021/acs.jmedchem.9b01155.
NLRP3 inflammasomes have recently emerged as an attractive drug target for neurodegenerative disorders. In our continuing studies, a new chemical scaffold was designed as selective inhibitors of NLRP3 inflammasomes. Initial characterization of the lead HL16 demonstrated improved, however, nonselective inhibition on the NLRP3 inflammasome. Structure-activity relationship studies of HL16 identified a new lead, 17 (YQ128), with an IC50 of 0.30 ± 0.01 μM. Further studies from in vitro and in vivo models confirmed its selective inhibition on the NLRP3 inflammasome and its brain penetration. Furthermore, pharmacokinetic studies in rats at 20 mg/kg indicated extensive systemic clearance and tissue distribution, leading to a half-life of 6.6 h. However, the oral bioavailability is estimated to be only 10%, which may reflect limited GI permeability and possibly high first-pass effects. Collectively, these findings strongly encourage development of more potent analogues with improved pharmacokinetic properties from this new chemical scaffold.