DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats.
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.
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan katsuya-fujita@ds-pharma.co.jp tetsuro-nariai@ds-pharma.co.jp.
Tetsuro
T
Nariai
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan katsuya-fujita@ds-pharma.co.jp tetsuro-nariai@ds-pharma.co.jp.
Katsuya
K
Fujita
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Kenji
K
Kawane
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Masaya
M
Mori
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Ryo
R
Nakayama
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Koichi
K
Matsuda
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Seiji
S
Katayama
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Nobuhisa
N
Fukuda
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Seiji
S
Hori
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Masato
M
Iwata
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Futoshi
F
Hasegawa
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Kuniko
K
Suzuki
Drug Research Division, Sumitomo Dainippon Pharma., Co., Ltd., Osaka, Japan.
Hiroshi
H
Kato
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D019556:COS Cells; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D000077545:Eplerenone; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D011188:Potassium / Q000097:blood*; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D012964:Sodium / Q000652:urine*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D015533:Transcriptional Activation
D000959:Antihypertensive Agents; D001549:Benzamides; D002257:Carbonic Anhydrase Inhibitors; C000600303:DSR-71167; D000451:Mineralocorticoid Receptor Antagonists; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D013449:Sulfonamides; D013148:Spironolactone; D000077545:Eplerenone; D012964:Sodium; D011188:Potassium