Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist
Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist
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DOI：
10.1016/j.ejphar.2015.06.015
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发表时间：
2015-08-15
影响因子：
5
通讯作者：
Sada, Toshio
中科院分区：
文献类型：
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作者：
Arai, Kiyoshi;Homma, Tsuyoshi;Sada, Toshio
本研究的目的是表征CS-3150，一种新的非甾体盐皮质激素受体拮抗剂的药理学特征。在放射性配体结合试验中，CS-3150抑制H-3-醛固酮与盐皮质激素受体结合，IC 50值为9.4 nM，其效力上级于螺内酯和依普利酮，其IC（50）分别为36和713 nM。CS-3150对盐皮质激素受体的选择性也比其他类固醇激素受体、糖皮质激素受体、雄激素受体和孕酮受体高至少1000倍。在报告基因试验中，CS-3150抑制醛固酮诱导的人盐皮质激素受体的转录激活，IC 50值为3.7 Oil，其效力上级于螺内酯和依普利酮，其IC（50）分别为66和970 nM。CS-3150对盐皮质激素受体没有激动作用，即使在5 μ M的高浓度下，对糖皮质激素受体、雄激素受体和孕酮受体也没有显示出任何拮抗或激动作用。在肾上腺切除大鼠中，CS-3150单次经口给药可抑制醛固酮诱导的尿Na+/K+比值（体内盐皮质激素受体活化的指标）降低，且这种抑制作用比螺内酯和依普利酮更有效且持续时间更长。CS-3150长期给药可抑制由醋酸脱氧皮质酮（DOCA）/盐负荷引起的大鼠血压升高，其降压作用强于螺内酯和依普利酮，表明CS-3150是一种选择性、高效、持久的盐皮质激素受体拮抗剂。该药物可用于治疗高血压、心血管和肾脏疾病。(C)© 2015 Elsevier B. V.版权所有
The present study was designed to characterize the pharmacological profile of CS-3150, a novel nonsteroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited H-3-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4 nM, and its potency was superior to that of spironolactone and eplerenone, whose IC(50)s were 36 and 713 nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7 Oil, and its potency was superior to that of spironolactone and eplerenone, whose IC(50)s were 66 and 970 nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5 mu M. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na+/K+ ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/saltloading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone.These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders. (C) 2015 Elsevier B.V. All rights reserved