SM-368229, a Novel Selective and Potent Non-steroidal Mineralocorticoid Receptor Antagonist With Strong Urinary Na+ Excretion Activity

Journal of Pharmacological Sciences

Katsuya Fujita²  Masaya Mori²  Seiji Katayama¹  Kazuki Matsui³  Seiji Hori¹  Tetsuro Nariai² 

[1] Chemistry Research Laboratory, Dainippon Sumitomo Pharma Co., Ltd., Japan;Pharmacology Research Laboratory, Dainippon Sumitomo Pharma Co., Ltd., Japan;Research Planning & Management, Dainippon Sumitomo Pharma Co., Ltd., Japan

关键词: mineralocorticoid receptor (MR);    aldosterone;    spironolactone;    eplerenone;    steroid hormone;   

DOI  :  10.1254/jphs.10285FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(29)Cited-By(23)Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for the treatment of hypertension and heart failure. However, the use of these two agents has been limited due to endocrine disturbance (SPI) and poor drug action (EPL). In our search for safer and more effective MR antagonists, we identified SM-368229 as a novel non-steroidal MR antagonist. SM-368229 showed strong MR inhibitory activity with IC50 values of 0.021 and 0.13 μM in the binding assay and reporter-gene assay, respectively. The selectivity of SM-368229 for MR was 18-fold higher than that for other steroid receptors, such as androgen, progesterone, and glucocorticoid receptors. SM-368229 dose-dependently increased urinary Na+/K+ ratio with an ED50 value of 5.6 mg/kg in adrenalectomized rats treated with deoxycorticosterone acetate, and its efficacy was superior to that of SPI (ED50 = 14 mg/kg) or EPL (ED50 = 147 mg/kg). Moreover, even at high doses of 100 and 300 mg/kg, SM-368229 showed very weak anti-androgenic effect in methyltestosterone-treated male rats and no progestagenic effect in estrus cycle synchronized female rats. These findings indicate that SM-368229 may offer a new promising therapeutic option for the treatment of hypertension and heart failure.

【 授权许可】

Unknown