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AER-271 is a novel and potent aquaporin-4 (AQP4) inhibitor that blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest. 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.
| Targets |
AER-271 (CAS#: 634913-39-6) is a prodrug that is converted to the active compound AER-270 (CAS#: 634913-38-5). The target is aquaporin-4 (AQP4). AER-270 is a selective, partial antagonist of AQP4. In a cell-based light scattering assay, AER-270 inhibited human AQP4-M23 with an IC50 of approximately 0.42 µM. It inhibited rat AQP4 with an IC50 of approximately 0.48 µM and mouse AQP4 with an IC50 of approximately 0.50 µM. [2]
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| ln Vitro |
AER-270, the active metabolite of AER-271 (CAS#: 634913-39-6), inhibited AQP4-mediated water permeability in CHO cells expressing human AQP4-M23. In a light scattering assay using a hyperosmotic shock (300 to 415 mOsm), AER-270 (10 µM) gave 47.0% inhibition of AQP4-mediated water permeability. [2]
In a video microscopy assay, CHO cells expressing AQP4 were exposed to a hypoosmotic shock (deionized water). AER-3, a related phenylbenzamide, reduced the rate of AQP4 cell swelling, giving ~84% inhibition. [2] In a Cell Volume Cytometry assay, CHO cells expressing AQP4 were exposed to a hypoosmotic shock (300 to 100 mOsm). AER-3 reduced the rate of cell volume change, giving ~72% inhibition. [2] AER-270 showed preferential inhibition of AQP4 over other aquaporins. In a light scattering assay at 10 µM, it inhibited AQP4-M1 by 44.9 ± 1.4% and AQP4-M23 by 48.8 ± 1.6%, while inhibiting AQP1 by 13.2 ± 1.1%, AQP5 by 4.5 ± 0.7%, and AQP2 was not determined. [2] |
| ln Vivo |
In vivo, endogenous phosphatases change AER-271 into AER-270. In a juvenile model of wild-type respiratory cardiac arrest, AER-271 causes cerebral edema and enhances early outcomes [1]. In an emergency animal model of cerebral stroke, AER-271 improves neurological outcomes and decreases cerebral edema. In a localized stroke model, administration of AER-271 (5 mg/kg; i.p.) resulted in better outcomes and decreased cerebral edema [2].
AER-271 (CAS#: 634913-39-6) treatment in a rat model of asphyxial cardiac arrest (CA) ameliorated early cerebral edema measured at 3 h after CA vs. vehicle treated rats, reducing edema by 82.1%. AER-271 treatment also attenuated early neurologic deficit score (NDS) at 3 h post-CA by 20% compared to vehicle. AER-271 treatment resulted in a 43% reduction in pyknotic degenerating neurons on H&E in the hippocampal CA1 region at 72 h post-CA, and a 49% reduction in CA1 hippocampal FluoroJade positivity. AER-271 treatment also resulted in a 55% reduction in Iba1 positivity (microglial response) in the CA1 hippocampus at 72 h post-CA. [1] In a mouse water intoxication model, co-injection of AER-270 (0.8 mg/kg, IP, in the water bolus) improved 4-hour survival to 50.5% compared to 15.3% for vehicle, representing a 3.3-fold improvement. AER-270 reduced the rate of cerebral edema formation by 2.5-fold as measured by MRI brain volume analysis. [2] In a mouse model of ischemic stroke (1 h MCAo), treatment with AER-271 (5 mg/kg IP every 3 hours starting 75 min after occlusion) improved neurological outcome at 24 hours (average score 0.89 ± 0.31 vs 2.50 ± 0.62 for vehicle). AER-271 treatment reduced cerebral edema, with a relative change in ipsilateral brain volume of 5.63 ± 1.75% compared to 15.01 ± 1.95% for vehicle, a 2.6-fold reduction. [2] In a rat model of ischemic stroke (1 h MCAo), IV infusion of AER-271 (loading dose of 4 mg/kg followed by maintenance dose of 0.03 mg/kg/hr) reduced cerebral edema from 23.8 ± 2.3% (vehicle) to 16.1 ± 1.8% and improved neurological outcome (modified Garcia score). A minimum effective maintenance dose of 0.03 mg/kg/hr was observed. [2] |
| Cell Assay |
In a light scattering assay, CHO cells expressing AQP4 or CD81 (control) were grown to confluence in 96-well plates. Cells were treated with vehicle (0.1% DMSO) or test compound (e.g., 10 µM AER-270) for 30 minutes. A hyperosmotic shock was induced by adding an equal volume of HBSS (530 mOsm) to achieve a final osmolarity of 415 mOsm. Light scattering was monitored by measuring absorbance at 600 nm using a multiplate reader. The rate of the initial rise in absorbance (cell shrinking) was used to calculate percent inhibition of AQP4-mediated water permeability. [2]
In a video microscopy assay, CHO cells expressing AQP4 or CD81 were seeded in 6-well plates and treated with vehicle or test compound for 30 minutes. Media was aspirated and replaced with deionized water to induce a hypoosmotic shock. Cell swelling was recorded using light microscopy at 100x magnification. Video files were analyzed using ImageJ to measure relative cell diameter (D/D0) over time. The initial rate of cell diameter increase was used to calculate percent inhibition. [2] In a Cell Volume Cytometry assay, CHO cells expressing AQP4 or CD81 were grown on glass coverslips and treated with vehicle or test compound. The coverslip was placed in a microfluidics chamber, and a hypoosmotic shock from 300 to 100 mOsm was applied. Cell swelling was monitored by measuring changes in electrical resistance (R/R0). The initial rate of resistance change was used to calculate percent inhibition. [2] |
| Animal Protocol |
Animal/Disease Models: Male mice (C57BL/6J, 8-12 weeks old, 25- 30 g) [2]
Doses: 5 mg/kg Route of Administration: intraperitoneal (ip) injection Treatment Experimental Results: Good effect, mean neurological score of 0.89 Compared with control mice receiving vehicle, mean neurological score of ±0.31 2.50±0.62. For the water intoxication model, mouse brain volumes were assessed using T2-weighted MRI. Sagittal images of the head were acquired using conventional spin echo (TR/TE = 3000/12 ms, resolution = 0.0195 cm/pixel, 3 averages, total scan time = 4 min 48 s) prior to water injection, at 5:40 min post water injection, and every 5:20 min thereafter until the animal expired. Brain volume was calculated by summing cross-sectional brain areas and multiplying by slice thickness (0.7 mm). [2] For the MCAo model, mouse brain volumes were assessed using T2-weighted MRI. Coronal images were acquired using conventional spin echo (TR/TE = 3000/12 ms, resolution = 0.0078 cm/pixel, 3 averages, total scan time = 9 min 36 s) after 24 hours of reperfusion. Volumes of ipsilateral and contralateral hemispheres were quantitated separately. Relative change in hemispheric brain volume was calculated as ((Vi - Vc)/Vc) × 100%. [2] For the rat MCAo model, a similar MRI protocol was used with a resolution of 0.0156 cm/pixel after 48 hours of reperfusion. [2] |
| ADME/Pharmacokinetics |
AER-271 (CAS#: 634913-39-6) is a prodrug that is converted in vivo to the active compound AER-270 (CAS#: 634913-38-5). After intraperitoneal (IP) administration of AER-271 at 10 mg/kg to mice, AER-270 reached peak plasma concentrations >500 ng/mL and peak brain tissue concentrations >100 ng/g. The estimated rate of IP absorption/conversion for AER-270 derived from AER-271 was 0.10 min⁻¹, and the elimination rate was 0.029 min⁻¹. [2]
In mice, after IP administration of AER-270 (0.8 mg/kg in water), peak plasma concentration of AER-270 was approximately 60 ng/mL. [2] In rats subjected to MCAo, continuous IV infusion of AER-271 was used. A loading dose of 4 mg/kg followed by a maintenance dose of 0.03 mg/kg/hr achieved a plasma concentration of AER-270 that reduced cerebral edema. Higher maintenance doses (0.1, 0.4, 2 mg/kg/hr) resulted in higher plasma concentrations of AER-270 (e.g., ~130 ng/mL at 0.4 mg/kg/hr, ~350 ng/mL at 2 mg/kg/hr). [2] In a pediatric asphyxial cardiac arrest model in rats, an IP loading bolus of AER-271 (5 mg/kg) at return of spontaneous circulation (ROSC) paired with a primed subcutaneous (SQ) osmotic continuous infusion pump (0.08 mg/h × 24 h) rapidly attained and maintained therapeutic drug levels (target plasma level of AER-270 was 70 ng/mL based on a mouse ischemic stroke model). Therapeutic levels were confirmed at 6 h (1475.99 ± 305.11 ng/mL) and 24 h (1699.37 ± 181.50 ng/mL). [1] |
| Toxicity/Toxicokinetics |
AER-271 (CAS#: 634913-39-6) treatment was well tolerated in a pediatric asphyxial cardiac arrest model in rats with no apparent effect on haemodynamics or serum chemistry. There were no differences in heart rate, mean arterial pressure, temperature, CPR duration, serum lactate, osmolarity, electrolytes, glucose, or hematocrit between AER-271-treated and vehicle-treated injury groups. [1]
AER-270 (1 or 10 µM) showed no inhibition of IKK-β or any other kinases in a panel of 456 kinases. Two known IKK-β inhibitors, PS-1145 and TPCA-1, failed to inhibit AQP4. [2] In a broad ligand screening assay (binding assays) investigating interactions with 80 different pharmacologically relevant targets (GPCRs, neurotransmitter receptors, ion channels), multiple potential off-target hits were observed for 1 or 2 µM AER-270, but these were not quantified. No inhibition of Cytochrome P450 was observed. [2] |
| References |
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| Molecular Formula |
C15H9CLF6NO5P
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|---|---|
| Molecular Weight |
463.6528
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| Exact Mass |
462.981
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| Elemental Analysis |
C, 38.86 H, 1.96 Cl, 7.65 F, 24.59 N, 3.02 O, 17.25 P, 6.68
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| CAS # |
634913-39-6
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| PubChem CID |
10412080
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| Appearance |
White to off-white solid powder
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| LogP |
3.5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
620
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])C(=C(C=1[H])C(N([H])C1C([H])=C(C(F)(F)F)C([H])=C(C(F)(F)F)C=1[H])=O)OP(=O)(O[H])O[H]
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| InChi Key |
WSHXPHFIHYXZKC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H9ClF6NO5P/c16-9-1-2-12(28-29(25,26)27)11(6-9)13(24)23-10-4-7(14(17,18)19)3-8(5-10)15(20,21)22/h1-6H,(H,23,24)(H2,25,26,27)
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| Chemical Name |
2-{[3,5-Bis(trifluoromethyl) phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
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| Synonyms |
AER 271 AER-271 AER271
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~269.60 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1568 mL | 10.7840 mL | 21.5680 mL | |
| 5 mM | 0.4314 mL | 2.1568 mL | 4.3136 mL | |
| 10 mM | 0.2157 mL | 1.0784 mL | 2.1568 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT03804476
Conditions:Stroke|Stroke, Acute|Stroke, IschemicProducts are for research use only; We do not sell to patients
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