DDO-7263
目录号 : GC64971
DDO-7263 是一种 1,2,4-Oxadiazole 衍生物，是一种有效的 Nrf2-ARE 激活剂。DDO-7263 通过与 Rpn6 结合上调 Nrf2，从而阻断 26S 蛋白酶体的组装和随后泛素化 Nrf2 的降解。DDO-7263 诱导 Nrf2 易位进入细胞核。DDO-7263 抑制 NLRP3 炎性体激活。DDO-7263 具有抗炎活性，并且有潜力用于神经退行性疾病(例如帕金森病 (PD)) 的研究。
Cas No.:2254004-96-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
DDO-7263, a 1,2,4-Oxadiazole derivative, is a potent Nrf2-ARE activator. DDO-7263 upregulates Nrf2 through binding to Rpn6 to block the assembly of 26S proteasome and the subsequent degradation of ubiquitinated Nrf2. DDO-7263 induces Nrf2 translocation into the nucleus. DDO-7263 inhibits of NLRP3 inflammasome activation. DDO-7263 exerts anti-inflammatory activity and has the potential for neurodegenerative diseases research, such as Parkinson's disease (PD)[1][2].
DDO-7263 (20 μM; 2-24 h) can upregulate the protein levels of HO-1 and NQO1 in concentration-dependent manners[1]. DDO-7263 (2.5, 5, 10, 20, 40, 80 μM; 24 h) can upregulate the survival rate of PC12 and THP-Ms cell after 400 μM H2O2 in a concentration-dependent manner. DDO-7263 alone has no significant decrease on cell survival rate[1].
DDO-7263 (10-100 mg/kg/day; IP; for 10 days) improves the behavioral abnormalities induced by MPTP in mice, significantly attenuates chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the substantia nigra (SN) and striatum of the mouse brain and inhibits the secretion of inflammatory factors[1]. DDO-7263 (7, 35, 70 mg/kg; IP) has a T1/2 of 3.32 hours and a Cmax of 1.38 mg/mL for rats[1].
[1]. Li-Li Xu, et al. 5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress. Free Radic Biol Med. 2019 Apr;134:288-303.
[2]. Zhen Dai, et al. Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome. J Med Chem. 2022 Mar 24;65(6):5029-5043.
| Cas No. | 2254004-96-9 | SDF | Download SDF |
| 分子式 | C14H9F2N3O | 分子量 | 273.24 |
| 溶解度 | DMSO : 17.86 mg/mL (65.36 mM; ultrasonic and warming and heat to 60°C) | 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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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.6598 mL | 18.2989 mL | 36.5979 mL |
| 5 mM | 0.732 mL | 3.6598 mL | 7.3196 mL |
| 10 mM | 0.366 mL | 1.8299 mL | 3.6598 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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2.
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5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress
Free Radic Biol Med 2019 Apr;134:288-303.PMID:30615919DOI:10.1016/j.freeradbiomed.2019.01.003.
Parkinson's disease (PD) is the second most common aging-related neurodegenerative disease worldwide. Oxidative stress and neuroinflammation are critical events in the degeneration of dopaminergic neurons in PD. In this study, we found that DDO-7263, a novel Nrf2-ARE activator reported by us, has ideal therapeutic effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. DDO-7263 improved the behavioral abnormalities induced by MPTP in mice, significantly attenuated chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the substantia nigra (SN) and striatum of the mouse brain and inhibited the secretion of inflammatory factors. In addition, DDO-7263 protected PC12 neurons from H2O2-induced oxidative damage. The neuroprotective effects of DDO-7263 were confirmed both in vitro and in vivo models. Further studies showed that the neuroprotective effect of DDO-7263 was mediated by the activation of Nrf2-ARE signaling pathway and the inhibition of NLRP3 inflammasome activation. DDO-7263 induced NLRP3 inflammasome inhibition is dependent on Nrf2 activation. This conclusion was also verified in THP-1-derived macrophages (THP-Ms). DDO-7263 significantly inhibited NLRP3 activation, cleaved caspase-1 production and IL-1β protein expression in ATP-LPS-exposed THP-Ms cells. The pharmacokinetic parameters and tissue distribution results indicated that DDO-7263 has a brain tissue targeting function. All these lines of evidence show that DDO-7263 has ideal therapeutic effects on neurodegenerative diseases such as PD.
Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome
J Med Chem 2022 Mar 24;65(6):5029-5043.PMID:35253427DOI:10.1021/acs.jmedchem.1c02210.
1,2,4-Oxadiazole derivatives, a class of Nrf2-ARE activators, exert an extensive therapeutic effect on inflammation, cancer, neurodegeneration, and microbial infection. Among these analogues, DDO-7263 is the most potent Nrf2 activator and used as the core structure for bioactive probes to explore the precise mechanism. In this work, we obtained compound 7, a mimic of DDO-7263, and biotin-labeled and fluorescein-based probes, which exhibited homologous biological activities to DDO-7263, including activating Nrf2 and its downstream target genes, anti-oxidative stress, and anti-inflammatory effects. Affinity chromatography and mass analysis techniques revealed Rpn6 as the potential target protein regulating the Nrf2 signaling pathway. In vitro affinity experiments further confirmed that DDO-7263 upregulated Nrf2 through binding to Rpn6 to block the assembly of 26S proteasome and the subsequent degradation of ubiquitinated Nrf2. These results indicated that Rpn6 is a promising candidate target to activate the Nrf2 pathway for protecting cells and tissues from oxidative, electrophilic, and exogenous microbial stimulation.
Palladium-Mediated Synthesis of [Carbonyl-11C]acyl Amidines from Aryl Iodides and Aryl Bromides and Their One-Pot Cyclization to 11C-Labeled Oxadiazoles
J Org Chem 2022 Dec 13.PMID:36512765DOI:10.1021/acs.joc.2c02102.
Positron emission tomography (PET) is a highly valuable imaging technique with many clinical applications. The possibility to study physiological and biochemical processes in vivo also makes PET an important tool in drug discovery. Of importance is the possibility of labelling the compound of interest with a positron-emitting radionuclide, such as carbon-11. Carbonylation reactions with [11C]carbon monoxide ([11C]CO) has been used to label a number of molecules containing a carbonyl derivative, such as amides and esters, with carbon-11. Presented herein is the palladium-mediated carbonylative synthesis of [carbonyl-11C]acyl amidines and their subsequent cyclization to 11C-labeled 1,2,4-oxadiazoles. Starting from amidines, [11C]CO, and either aryl iodides or aryl bromides, [carbonyl-11C]acyl amidines were synthesized and isolated in good to very good radiochemical yields (RCY). The 11C-labeled 1,2,4-oxadiazoles were synthesized without the isolation of the intermediate [carbonyl-11C]acyl amidines and isolated in useful RCYs, including the NF-E2-related factor 2 activator DDO-7263. 3-Phenyl-5-(4-tolyl)-1,2,4-(5-11C)oxadiazole was synthesized and isolated with a clinically relevant molar activity. The broadened substrate scope, together with the good RCY and high Am, demonstrates the utility of this method for the incorporation of carbon-11 into acyl amidines and 1,2,4-oxadiazoles, structural motifs of pharmacological interest.