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]。