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 IC(50) 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 ED(50) value of 5.6 mg/kg in adrenalectomized rats treated with deoxycorticosterone acetate, and its efficacy was superior to that of SPI (ED(50) = 14 mg/kg) or EPL (ED(50) = 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.

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist, on the blood pressure and cardiorenal injury markers in aldosterone/salt-treated hypertensive rats, in comparison to those of spironolactone (SPI). Uninephrectomized rats, given 1% NaCl to drink, were infused with aldosterone (0.75 µg/h, s.c.). In experiment 1, SM-368229 (10, 30 mg/kg) or SPI (100 mg/kg) were administered for 14 days immediately after aldosterone/salt loading. In experiment 2, SM-368229 (10 mg/kg) or SPI (100 mg/kg) were administered for 10 days after 10 days of aldosterone/salt loading. In both experiments, SM-368229 prevented the increase in systolic blood pressure, heart/kidney weights, and urinary protein/N-acetyl-β-D- glucosaminidase excretion caused by aldosterone infusion. In real-time polymerase chain reaction analysis, SM-368229 abolished aldosterone-induced gene expression levels for inflammatory, fibrosis and oxidative stress markers in hearts and kidneys. The antihypertensive effect of SM-368229 (30 mg/kg) was superior to that of SPI, and the antihypertensive and cardiorenal protective effects of SM-368229 (10 mg/kg) were similar to those of SPI (100 mg/kg) in both experiments. These results clearly demonstrated that SM-368229 strongly attenuated the progression of hypertension and exerted cardiorenal protection in aldosterone/salt-treated hypertensive rats.

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The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist with partial agonistic activity, and spironolactone (SPI) on systolic blood pressure (SBP) and serum potassium in spontaneously hypertensive rats. SM-368229 given for 2 weeks prevented the increase in SBP without serum potassium elevation, but the treatment with SPI prevented SBP increase with serum potassium elevation. To elucidate the contribution of partial agonistic activity of SM-368229 for MR in the mitigation of serum potassium elevation, we studied the relationships between sodium balance decrease, as an index of antimineralocorticoid action, and serum potassium elevation in adrenalectomized and/or potassium-loaded rats, using SM-368229 and its derivatives (DSR-11861 and DSR-14397) showing different partial agonist activities for MR (12%, 0%, and 36%, respectively). DSR-11861 and SPI reversed sodium balance and increased serum potassium. SM-368229 also reversed sodium balance but did not show apparent serum potassium increase. Although DSR-14397 did not show serum potassium increase, its antimineralocorticoid action was very weak. These findings indicate that serum potassium elevation is negatively related to partial agonistic activities for MR, and SM-368229 shows antihypertensive efficacy with minimal effect on serum potassium level, probably due to its partial agonistic property.

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