AER-271
目录号 : GC39549AER-271 是 AER-270 的膦酸酯前药。AER-271 是一种 aquaporin-4 (AQP4) 抑制剂,有潜力用于急性缺血性中风的研究。
Cas No.:634913-39-6
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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AER-271, a phosphonate prodrug derivative of AER-270, is an aquaporin-4 (AQP4) inhibitor for the research of acute ischemic stroke[1].
[1]. Wallisch JS, et al. The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest. Pediatr Res. 2019 Mar;85(4):511-517. [2]. Farr GW, et al. Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury. Neuroscience. 2019 Apr 15;404:484-498.
Cas No. | 634913-39-6 | SDF | |
Canonical SMILES | O=C(NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1)C2=CC(Cl)=CC=C2OP(O)(O)=O | ||
分子式 | C15H9ClF6NO5P | 分子量 | 463.65 |
溶解度 | DMSO: 125 mg/mL (269.60 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.1568 mL | 10.784 mL | 21.568 mL |
5 mM | 0.4314 mL | 2.1568 mL | 4.3136 mL |
10 mM | 0.2157 mL | 1.0784 mL | 2.1568 mL |
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2.
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The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest
Pediatr Res 2019 Mar;85(4):511-517.PMID:30367162DOI:10.1038/s41390-018-0215-5.
Background: Cerebral edema after cardiac arrest (CA) is associated with increased mortality and unfavorable outcome in children and adults. Aquaporin-4 mediates cerebral water movement and its absence in models of ischemia improves outcome. We investigated early and selective pharmacologic inhibition of aquaporin-4 in a clinically relevant asphyxial CA model in immature rats in a threshold CA insult that produces primarily cytotoxic edema in the absence of blood-brain barrier permeability. Methods: Postnatal day 16-18 Sprague-Dawley rats were studied in our established 9-min asphyxial CA model. Rats were randomized to aquaporin-4 inhibitor (AER-271) vs vehicle treatment, initiated at return of spontaneous circulation. Cerebral edema (% brain water) was the primary outcome with secondary assessments of the Neurologic Deficit Score (NDS), hippocampal neuronal death, and neuroinflammation. Results: Treatment with AER-271 ameliorated early cerebral edema measured at 3 h after CA vs vehicle treated rats. This treatment also attenuated early NDS. In contrast to rats treated with vehicle after CA, rats treated with AER-271 did not develop significant neuronal death or neuroinflammation as compared to sham. Conclusion: Early post-resuscitation aquaporin-4 inhibition blocks the development of early cerebral edema, reduces early neurologic deficit, and blunts neuronal death and neuroinflammation post-CA.
Operation Brain Trauma Therapy: 2016 Update
Mil Med 2018 Mar 1;183(suppl_1):303-312.PMID:29635589DOI:10.1093/milmed/usx184.
Operation brain trauma therapy (OBTT) is a multi-center, pre-clinical drug and biomarker screening consortium for traumatic brain injury (TBI). Therapies are screened across three rat models (parasagittal fluid percussion injury, controlled cortical impact [CCI], and penetrating ballistic-like brain injury). Operation brain trauma therapy seeks to define therapies that show efficacy across models that should have the best chance in randomized clinical trials (RCTs) and/or to define model-dependent therapeutic effects, including TBI protein biomarker responses, to guide precision medicine-based clinical trials in targeted pathologies. The results of the first five therapies tested by OBTT (nicotinamide, erythropoietin, cyclosporine [CsA], simvastatin, and levetiracetam) were published in the Journal of Neurotrauma. Operation brain trauma therapy now describes preliminary results on four additional therapies (glibenclamide, kollidon-VA64, AER-271, and amantadine). To date, levetiracetam was beneficial on cognitive outcome, histology, and/or biomarkers in two models. The second most successful drug, glibenclamide, improved motor function and histology in CCI. Other therapies showed model-dependent effects (amantadine and CsA). Critically, glial fibrillary acidic protein levels predicted treatment effects. Operation brain trauma therapy suggests that levetiracetam merits additional pre-clinical and clinical evaluation and that glibenclamide and amantadine merit testing in specific TBI phenotypes. Operation brain trauma therapy has established that rigorous, multi-center consortia could revolutionize TBI therapy and biomarker development.
Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury
Neuroscience 2019 Apr 15;404:484-498.PMID:30738082DOI:10.1016/j.neuroscience.2019.01.034.
Cerebral edema in ischemic stroke can lead to increased intracranial pressure, reduced cerebral blood flow and neuronal death. Unfortunately, current therapies for cerebral edema are either ineffective or highly invasive. During the development of cytotoxic and subsequent ionic cerebral edema water enters the brain by moving across an intact blood brain barrier and through aquaporin-4 (AQP4) at astrocyte endfeet. Using AQP4-expressing cells, we screened small molecule libraries for inhibitors that reduce AQP4-mediated water permeability. Additional functional assays were used to validate AQP4 inhibition and identified a promising structural series for medicinal chemistry. These efforts improved potency and revealed a compound we designated AER-270, N-[3,5-bis (trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. AER-270 and a prodrug with enhanced solubility, AER-271 2-{[3,5-Bis(trifluoromethyl) phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, improved neurological outcome and reduced swelling in two models of CNS injury complicated by cerebral edema: water intoxication and ischemic stroke modeled by middle cerebral artery occlusion.