Document Detail

SM-368229, a novel selective and potent non-steroidal mineralocorticoid receptor antagonist with strong urinary Na+ excretion activity.
MedLine Citation:
PMID:  21358118     Owner:  NLM     Status:  MEDLINE    
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.
Tetsuro Nariai; Katsuya Fujita; Masaya Mori; Seiji Katayama; Seiji Hori; Kazuki Matsui
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Publication Detail:
Type:  Journal Article     Date:  2011-02-24
Journal Detail:
Title:  Journal of pharmacological sciences     Volume:  115     ISSN:  1347-8648     ISO Abbreviation:  J. Pharmacol. Sci.     Publication Date:  2011  
Date Detail:
Created Date:  2011-03-23     Completed Date:  2011-10-21     Revised Date:  2013-11-25    
Medline Journal Info:
Nlm Unique ID:  101167001     Medline TA:  J Pharmacol Sci     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  346-53     Citation Subset:  IM    
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MeSH Terms
Area Under Curve
Benzoxazines / chemistry,  pharmacokinetics,  pharmacology*
COS Cells
Cercopithecus aethiops
Drug Evaluation, Preclinical
Estrus / drug effects
Hypertension / drug therapy*
Mineralocorticoid Receptor Antagonists* / chemistry,  pharmacology
Potassium / urine
Prostate / drug effects
Rats, Sprague-Dawley
Receptors, Glucocorticoid / genetics
Receptors, Mineralocorticoid / genetics,  metabolism
Seminal Vesicles / drug effects
Sodium / urine*
Spironolactone / analogs & derivatives,  chemistry,  pharmacology
Sulfonamides / chemistry,  pharmacokinetics,  pharmacology*
Reg. No./Substance:
0/Benzoxazines; 0/Mineralocorticoid Receptor Antagonists; 0/N-4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylthiophene-2-sulfonamide; 0/Receptors, Glucocorticoid; 0/Receptors, Mineralocorticoid; 0/Sulfonamides; 27O7W4T232/Spironolactone; 6995V82D0B/eplerenone; 9NEZ333N27/Sodium; RWP5GA015D/Potassium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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