title: SM-368229, a novel selective and potent non-steroidal mineralocorticoid receptor antagonist with strong urinary Na+ excretion activity.
abstract: 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.
authors.affiliation: Pharmacology Research Laboratory, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Nariai
authors.forename: Katsuya
authors.initials: K
authors.lastname: Fujita
authors.forename: Masaya
authors.initials: M
authors.lastname: Mori
authors.forename: Seiji
authors.initials: S
authors.lastname: Katayama
authors.forename: Seiji
authors.initials: S
authors.lastname: Hori
authors.forename: Kazuki
authors.initials: K
authors.lastname: Matsui
mesh_terms: D000818:Animals; D019540:Area Under Curve; D048588:Benzoxazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D000077545:Eplerenone; D004971:Estrus / Q000187:drug effects; D005260:Female; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D011188:Potassium / Q000652:urine; D011467:Prostate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D012669:Seminal Vesicles / Q000187:drug effects; D012964:Sodium / Q000652:urine*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D048588:Benzoxazines; D000451:Mineralocorticoid Receptor Antagonists; C561881:N-4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylthiophene-2-sulfonamide; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013449:Sulfonamides; D013148:Spironolactone; D000077545:Eplerenone; D012964:Sodium; D011188:Potassium