Nariai Tetsuro, Fujita Katsuya, Kawane Kenji, Mori Masaya, Nakayama Ryo, Matsuda Koichi, Katayama Seiji, Fukuda Nobuhisa, Hori Seiji, Iwata Masato, Hasegawa Futoshi, Suzuki Kuniko, Kato Hiroshi
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
J Pharmacol Exp Ther. 2015 Jul;354(1):2-9. doi: 10.1124/jpet.114.221341. Epub 2015 Apr 28.
Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for treating hypertension and heart failure. However, these two agents have the serious side effect of hyperkalemia. We hypothesized that adding the ability to inhibit carbonic anhydrase (CA) would reduce the risk of hyperkalemia associated with MR antagonists. We investigated the profiles of DSR-71167 [2-([(2,2-difluoroethyl)amino]methyl)-2'-fluoro-N-(3-methoxy-4-sulfamoylphenyl)biphenyl-4-carboxamide hydrochloride; an MR antagonist with weak CA inhibitory activity] with regard to antimineralocorticoid actions by examining relationships between the urinary excretion of sodium (index of antimineralocorticoid action) in deoxycorticosterone acetate-treated rats and elevation of serum levels of potassium in potassium-loaded rats compared with a DSR-71167 derivative without CA inhibition (2-(hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide), SPI, and EPL. DSR-71167 dose-dependently increased urinary excretion of sodium in deoxycorticosterone acetate-treated rats without elevating serum levels of potassium in potassium-loaded rats. 2-(Hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide, SPI, and EPL elevated serum levels of potassium significantly in potassium-loaded rats at doses that increased MR inhibitory activity. We confirmed that DSR-71167 significantly increases urinary bicarbonate and decreases blood bicarbonate, as pharmacodynamic markers of CA inhibition, in intact rats. Chronic DSR-71167 administration showed antihypertensive effects in high salt-loaded Dahl hypertensive rats. These results demonstrate that DSR-71167 is a novel type of MR antagonist, with CA inhibitory activity, which is expected to become a safer MR antagonist with a low potential risk for hyperkalemia.
盐皮质激素受体（MR）拮抗剂，如螺内酯（SPI）和依普利酮（EPL），可用于治疗高血压和心力衰竭。然而，这两种药物具有高钾血症这一严重副作用。我们推测，增加抑制碳酸酐酶（CA）的能力将降低与MR拮抗剂相关的高钾血症风险。我们通过检查醋酸脱氧皮质酮处理的大鼠尿钠排泄量（抗盐皮质激素作用指标）与钾负荷大鼠血清钾水平升高之间的关系，研究了DSR-71167[2-([(2,2-二氟乙基)氨基]甲基)-2'-氟-N-(3-甲氧基-4-氨磺酰基苯基)联苯-4-甲酰胺盐酸盐；一种具有弱CA抑制活性的MR拮抗剂]的抗盐皮质激素作用概况，并与无CA抑制作用的DSR-71167衍生物（2-(羟甲基)-N-[4-(甲基磺酰基)phenyl]-2'-(三氟甲基)联苯-4-甲酰胺）、SPI和EPL进行比较。DSR-71167在醋酸脱氧皮质酮处理的大鼠中剂量依赖性地增加尿钠排泄，而在钾负荷大鼠中不升高血清钾水平。2-(羟甲基)-N-[4-(甲基磺酰基)phenyl]-2'-(三氟甲基)联苯-4-甲酰胺、SPI和EPL在增加MR抑制活性的剂量下，使钾负荷大鼠的血清钾水平显著升高。我们证实，在完整大鼠中，作为CA抑制的药效学标志物，DSR-71167显著增加尿碳酸氢盐并降低血碳酸氢盐。长期给予DSR-71167对高盐负荷的Dahl高血压大鼠具有降压作用。这些结果表明，DSR-71167是一种新型的具有CA抑制活性的MR拮抗剂，有望成为一种更安全、高钾血症潜在风险低的MR拮抗剂。
