Esaxerenone
(Synonyms: 艾沙利酮,CS-3150; XL-550) 目录号 : GC19143
Esaxerenone (CS-3150) 是一种选择性的非甾体类盐皮质激素受体拮抗剂，已显示可与盐皮质激素受体结合，从而抑制醛固酮结合和受体激活 。
Cas No.:1632006-28-0
Sample solution is provided at 25 µL, 10mM.
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Esaxerenone (CS-3150), a selective nonsteroidal mineralocorticoid receptor antagonist, has been shown to bind to mineralocorticoid receptors, thereby inhibiting aldosterone binding and activation of the receptor [1]. Esaxerenone inhibited 3H-aldosterone binding to mineralocorticoid receptor in a concentration-dependent manner with IC50 of 9.4 nM. Esaxerenone inhibited aldosterone-induced human mineralocorticoid receptor activation in a concentration-dependent manner with IC50 of 3.7 nM. Esaxerenone showed antagonist activity for rat mineralocorticoid receptor with IC50 of 4.9 nM [1].
Esaxerenone (10,100nM) reversed the reduction in insulin-induced Akt phosphorylation caused by aldosterone in insulin target cells, such as adipocytes, hepatocytes, and myocytes. Pretreatment with esaxerenone significantly ameliorated insulin signaling in these cell types [2].
Esaxerenone (3 mg/kg) significantly inhibited DOCA/salt-loading induced elevation in systolic blood pressure compared with the control rats (DOCA-untreated) [1]. Esaxerenone (0.25-2 mg/kg) was orally administered once a day to DS rats fed a high salt diet for 7 weeks. The high salt diet significantly increased systolic blood pressure, which was prevented by treatment with Esaxerenone in a dose-dependent manner with no hyperkalemia (>5.5 mEq/L). Esaxerenone also suppressed proteinuria and renal hypertrophy induced by the high salt diet. Histopathological examination of kidneys showed that CS-3150 markedly ameliorated glomerulosclerosis, tubular injury and tubulointerstitial fibrosis. CS-3150 inhibited left ventricular hypertrophy and elevation of plasma brain natriuretic peptide level [3]. In preclinical models, the pharmacokinetic profile of esaxerenone is the basis for a long-lasting action (plasma half-life rats: 6.5-6.9 h), high oral bioavailability and predominant excretion via faeces [1,4]. A long plasma half-life of esaxerenone has been confirmed in healthy human volunteers (plasma half-life: 30 h) [5].
References:
[1].?Arai K, Homma T, Morikawa Y, et al. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist[J]. European Journal of Pharmacology, 2015, 761: 226-234.
[2].?Bavuu O, Fukuda D, Ganbaatar B, et al. Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet[J]. European Journal of Pharmacology, 2022, 931: 175190.
[3].?Arai K, Tsuruoka H, Homma T. CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats[J]. European journal of pharmacology, 2015, 769: 266-273.
[4].?Wan N, Rahman A, Nishiyama A. Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease[J]. Journal of Human Hypertension. 2021 Feb;35(2):148-56.
[5].?Yamada, M., Mendell, J., Takakusa, H., Shimizu, T., & Ando, O. (2019). Pharmacokinetics, metabolism, and excretion of [14C] esaxerenone, a novel mineralocorticoid receptor blocker in humans[J]. Drug Metabolism and Disposition, 47(3), 340-349. Diseases, 2013, 72(Suppl 3): A129-A129.
Esaxerenone (CS-3150) 是一种选择性的非甾体类盐皮质激素受体拮抗剂，已显示可与盐皮质激素受体结合，从而抑制醛固酮结合和受体激活 [1]。 Esaxerenone 以浓度依赖性方式抑制 3H-醛固酮与盐皮质激素受体的结合，IC50 为 9.4 nM。 Esaxerenone 以浓度依赖性方式抑制醛固酮诱导的人盐皮质激素受体激活，IC50 为 3.7 nM。 Esaxerenone对大鼠盐皮质激素受体具有拮抗作用，IC50为4.9 nM [1]。
Esaxerenone (10,100nM) 可逆转胰岛素靶细胞（如脂肪细胞、肝细胞和肌细胞）中醛固酮引起的胰岛素诱导的 Akt 磷酸化减少。在这些细胞类型中用艾萨雷酮预处理可显着改善胰岛素信号[2]。
与对照大鼠（DOCA 未处理）相比，Esaxerenone (3 mg/kg) 显着抑制 DOCA/盐负荷引起的收缩压升高[1]。 Esaxerenone (0.25-2 mg/kg) 每天一次口服给喂食高盐饮食 7 周的 DS 大鼠。高盐饮食会显着增加收缩压，这可以通过以剂量依赖性方式使用 Esaxerenone 治疗来预防，并且没有出现高钾血症 (>5.5 mEq/L)。 Esaxerenone 还抑制高盐饮食引起的蛋白尿和肾肥大。肾脏的组织病理学检查表明，CS-3150 显着改善了肾小球硬化、肾小管损伤和肾小管间质纤维化。 CS-3150 抑制左心室肥大和血浆脑利钠肽水平升高[3]。在临床前模型中，esaxerenone 的药代动力学特性是持久作用（血浆半衰期大鼠:6.5-6.9 小时）、高口服生物利用度和主要通过粪便排泄的基础 [1,4]。 esaxerenone 的长血浆半衰期已在健康人类志愿者中得到证实（血浆半衰期:30 小时）[5]。
| Cell experiment [1]: | |
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Cell lines |
3T3-L1 preadipocytes, The human hepatoma cell line HepG2, Differentiated C2C12 myotubes |
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Preparation Method |
The cells were starved in DMEM containing 0.1% charcoal/dextran-treated FBS for 24 h, before stimulation with aldosterone. Cells were pretreated with 10 or 100 nM esaxerenone for 8 h before aldosterone treatment. The effects of aldosterone on insulin signaling were examined in cells treated with 100 or 1000 nM aldosterone for 4 h. Insulin signaling in these cell types was examined after stimulation with 17 nM insulin for 15 min. |
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Reaction Conditions |
10 or 100 nM for 8 hours |
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Applications |
Aldosterone significantly abrogated insulin signaling, as determined by insulin-induced Akt phosphorylation in insulin target cells, 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes, in a dose-dependent manner. Pretreatment with esaxerenone significantly ameliorated insulin signaling in these cell types. |
| Animal experiment [2]: | |
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Animal models |
Male Sprague-Dawley (SD) rats |
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Preparation Method |
Esaxerenone (0.3, 1 and 3 mg/kg), dissolved in N,N-dimethylacetamide (DMA):Tween 80:saline solution in a ratio of 1:1:8 (v/v/v), was orally administered to eight-week-old male SD rats. Blood samples were collected from the cervical vein at 0.25, 0.5, 1, 2, 4, 6, 8, 24 and 48 h after administration, and drug concentrations in plasma were measured by liquid chromatography-tandem mass spectrometry and API3000. |
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Dosage form |
0.3, 1 and 3 mg/kg, oral |
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Applications |
Single oral administration of Esaxerenone at 0.3, 1 and 3 mg/kg, the tmax was 2.0-4.5 h and t1/2 was 6.5-6.9 h. The Cmax and area under the curve to infinity (AUC0-inf) were dose-dependently increased. |
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References: [1]: Bavuu O, Fukuda D, Ganbaatar B, et al. Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet[J]. European Journal of Pharmacology, 2022, 931: 175190. |
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| Cas No. | 1632006-28-0 | SDF | |
| 别名 | 艾沙利酮,CS-3150; XL-550 | ||
| Canonical SMILES | O=C(C1=CN(CCO)C(C2=CC=CC=C2C(F)(F)F)=C1C)NC3=CC=C(S(=O)(C)=O)C=C3 | ||
| 分子式 | C22H21F3N2O4S | 分子量 | 466.47 |
| 溶解度 | DMSO : ≥ 125 mg/mL (267.97 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 | 2.1438 mL | 10.7188 mL | 21.4376 mL |
| 5 mM | 0.4288 mL | 2.1438 mL | 4.2875 mL |
| 10 mM | 0.2144 mL | 1.0719 mL | 2.1438 mL |
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| 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；
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2.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
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