Senicapoc
(Synonyms: 4-氟-A-(4-氟苯基)-A-苯基-苯甲酰胺,ICA-17043) 目录号 : GC37628
An inhibitor of IKCa1/KCa3.1 channels
Cas No.:289656-45-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | The whole blood is initially diluted 1:1 with Modified Flux Buffer (MFB), consisting of 140 mM NaCl, 5 mM KCl, 10 mM Tris (tris(hydroxymethyl)aminomethane), 0.1 mM EGTA (ethyleneglycoltetraacetic acid) (pH=7.4). The blood is centrifuged at 1000 rpm, and the pellet comprised primarily of RBCs is washed 3 times with MFB. The cells are then loaded with 86Rb+ by incubating the washed cells with 86Rb+ at a final concentration of 0.185 MBq/mL (5 μCi/mL) in MFB for at least 3 hours at 37°C. After loading with 86Rb+, the RBCs are washed 3 times with chilled MFB. The cells are then incubated for 10 minutes with test compound (senicapoc) at concentrations that ranged from 1 nM to 10 000 nM. Efflux of 86Rb+ is initiated by raising intracellular calcium levels in the RBCs with the addition of CaCl2 and A23187 (a calcium ionophore) to final concentrations of 2 mM and 5 μM, respectively. After 10 minutes of incubation at room temperature, the RBCs are pelleted in a microcentrifuge, and the supernatant is removed and counted in a Wallac MicroBeta liquid scintillation counter. |
Animal experiment: | Transgenic Hbbsingle/single SAD1 (SAD) female and male mice between 3 and 6 months of age, weighing 25 to 30 g, are used for this study. The SAD mice are divided into 2 groups, and either vehicle (n=6) or senicapoc (10 mg/kg) (n=6) is administered orally by gavage twice daily. C57B6/2J mice are used as controls (wild-type mice). Hematologic parameters are evaluated at baseline and after 11 and 21 days of therapy. Blood sampling and vehicle administration have previously been shown not to affect the blood parameters measured in this study. |
References: [1]. Stocker JW, et al. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood. 2003 Mar 15;101(6):2412-8. | |
Senicapoc is an inhibitor of intermediate conductance calcium-activated potassium (IKCa1/KCa3.1) channels.1,2 It inhibits rubidium efflux from and dehydration of isolated human red blood cells (RBCs) induced by the calcium ionophore A23187 .1 Senicapoc (10 mg/kg twice per day) reduces IKCa1/KCa3.1 channel activity, increases potassium levels in RBCs, and decreases erythrocyte density in the SAD transgenic mouse model of sickle cell disease. It inhibits IL-2, IFN-γ, IL-12, and IL-17A production in CD3+ T cells stimulated with phorbol 12-myristate 13-acetate and ionomycin when used at a concentration of 1 μM.3 Senicapoc (100 mg/kg) increases the paw withdrawal threshold in a rat model of chronic constriction injury (CCI) of the sciatic nerve.2
1.Stocker, J.W., De Franceschi, L., McNaughton-Smith, G.A., et al.ICA-17043, a novel gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD miceBlood101(6)2412-2418(2003) 2.Staal, R.G.W., Khayrullina, T., Zhang, H., et al.Inhibition of the potassium channel KCa 3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injuryEur. J. Pharmacol.7951-7(2017) 3.Hansen, L.K., Sevelsted-M?ller, L., Rabjerg, M., et al.Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitisJ. Crohns Colitis8(11)1378-1391(2014)
| Cas No. | 289656-45-7 | SDF | |
| 别名 | 4-氟-A-(4-氟苯基)-A-苯基-苯甲酰胺,ICA-17043 | ||
| Canonical SMILES | O=C(C(C1=CC=CC=C1)(C2=CC=C(C=C2)F)C3=CC=C(F)C=C3)N | ||
| 分子式 | C20H15F2NO | 分子量 | 323.34 |
| 溶解度 | DMSO: 50 mg/mL (154.64 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 | 3.0927 mL | 15.4636 mL | 30.9272 mL |
| 5 mM | 0.6185 mL | 3.0927 mL | 6.1854 mL |
| 10 mM | 0.3093 mL | 1.5464 mL | 3.0927 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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。
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Senicapoc treatment in COVID-19 patients with severe respiratory insufficiency-A randomized, open-label, phase II trial
Acta Anaesthesiol Scand 2022 Aug;66(7):838-846.PMID:35403225DOI:10.1111/aas.14072.
Background: The aim of the current study was to determine if treatment with Senicapoc, improves the PaO2 /FiO2 ratio in patients with COVID-19 and severe respiratory insufficiency. Methods: Investigator-initiated, randomized, open-label, phase II trial in four intensive care units (ICU) in Denmark. We included patients aged ≥18 years and admitted to an ICU with severe respiratory insufficiency due to COVID-19. The intervention consisted of 50 mg enteral Senicapoc administered as soon as possible after randomization and again after 24 h. Patients in the control group received standard care only. The primary outcome was the PaO2 /FiO2 ratio at 72 h. Results: Twenty patients were randomized to Senicapoc and 26 patients to standard care. Important differences existed in patient characteristics at baseline, including more patients being on non-invasive/invasive ventilation in the control group (54% vs. 35%). The median Senicapoc concentration at 72 h was 62.1 ng/ml (IQR 46.7-71.2). The primary outcome, PaO2 /FiO2 ratio at 72 h, was significantly lower in the Senicapoc group (mean 19.5 kPa, SD 6.6) than in the control group (mean 24.4 kPa, SD 9.2) (mean difference -5.1 kPa [95% CI -10.2, -0.04] p = .05). The 28-day mortality in the Senicapoc group was 2/20 (10%) compared with 6/26 (23%) in the control group (OR 0.36 95% CI 0.06-2.07, p = .26). Conclusions: Treatment with Senicapoc resulted in a significantly lower PaO2 /FiO2 ratio at 72 h with no differences for other outcomes.
Senicapoc: Repurposing a Drug to Target Microglia KCa3.1 in Stroke
Neurochem Res 2017 Sep;42(9):2639-2645.PMID:28364331DOI:10.1007/s11064-017-2223-y.
Stroke is the leading cause of serious long-term disability and the fifth leading cause of death in the United States. Treatment options for stroke are few in number and limited in efficacy. Neuroinflammation mediated by microglia and infiltrating peripheral immune cells is a major component of stroke pathophysiology. Interfering with the inflammation cascade after stroke holds the promise to modulate stroke outcome. The calcium activated potassium channel KCa3.1 is expressed selectively in the injured CNS by microglia. KCa3.1 function has been implicated in pro-inflammatory activation of microglia and there is recent literature suggesting that this channel is important in the pathophysiology of ischemia/reperfusion (stroke) related brain injury. Here we describe the potential of repurposing Senicapoc, a KCa3.1 inhibitor, to intervene in the inflammation cascade that follows ischemia/reperfusion.
Treatment with Senicapoc in a porcine model of acute respiratory distress syndrome
Intensive Care Med Exp 2021 Apr 19;9(1):20.PMID:33870468DOI:10.1186/s40635-021-00381-z.
Background: Senicapoc is a potent and selective blocker of KCa3.1, a calcium-activated potassium channel of intermediate conductance. In the present study, we investigated whether there is a beneficial effect of Senicapoc in a large animal model of acute respiratory distress syndrome (ARDS). The primary end point was the PaO2/FiO2 ratio. Methods: ARDS was induced in female pigs (42-49 kg) by repeated lung lavages followed by injurious mechanical ventilation. Animals were then randomly assigned to vehicle (n = 9) or intravenous Senicapoc (10 mg, n = 9) and received lung-protective ventilation for 6 h. Results: Final Senicapoc plasma concentrations were 67 ± 18 nM (n = 9). Senicapoc failed to change the primary endpoint PaO2/FiO2 ratio (Senicapoc, 133 ± 23 mmHg; vehicle, 149 ± 68 mmHg). Lung compliance remained similar in the two groups. Senicapoc reduced the level of white blood cells and neutrophils, while the proinflammatory cytokines TNFα, IL-1β, and IL-6 in the bronchoalveolar lavage fluid were unaltered 6 h after induction of the lung injury. Senicapoc-treatment reduced the level of neutrophils in the alveolar space but with no difference between groups in the cumulative lung injury score. Histological analysis of pulmonary hemorrhage indicated a positive effect of Senicapoc on alveolar-capillary barrier function, but this was not supported by measurements of albumin content and total protein in the bronchoalveolar lavage fluid. Conclusions: In summary, Senicapoc failed to improve the primary endpoint PaO2/FiO2 ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.
Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia
Expert Opin Investig Drugs 2009 Feb;18(2):231-9.PMID:19236269DOI:10.1517/13543780802708011.
Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Despite the lack of a reduction in the frequency of pain episodes, the increasing recognition that hemolysis contributes to the development of several SCD-related complications suggests that by decreasing hemolysis, Senicapoc may yet prove to be beneficial in this disease.
Treatment with Senicapoc, a KCa 3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome
Br J Pharmacol 2022 May;179(10):2175-2192.PMID:34623632DOI:10.1111/bph.15704.
Background and purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (KCa 3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental approach: KCa 3.1 channel knockout (Kccn4-/- ) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the KCa 3.1 channel inhibitor, Senicapoc. The outcomes were oxygenation (PaO2 /FiO2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO2 /FiO2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4-/- mice. Pretreatment with Senicapoc (10-70 mg·kg-1 ) prevented the reduction in PaO2 /FiO2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg-1 ) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg-1 Senicapoc also improved the PaO2 /FiO2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, Senicapoc decreased TNF-α-induced permeability. Conclusions and implications: Genetic deficiency of KCa 3.1 channels and Senicapoc improved the PaO2 /FiO2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, Senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking KCa 3.1 channels is a potential treatment in ARDS-like disease.