EPLERENONE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H30O6
Molecular Weight	414.4914
Optical Activity	UNSPECIFIED
Defined Stereocenters	8 / 8
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12C[C@@]3(C)[C@@]([H])(CC[C@@]34CCC(=O)O4)[C@]5([H])[C@@H](CC6=CC(=O)CC[C@]6(C)[C@@]15O2)C(=O)OC

InChI

InChIKey=JUKPWJGBANNWMW-VWBFHTRKSA-N

InChI=1S/C24H30O6/c1-21-7-4-14(25)10-13(21)11-15(20(27)28-3)19-16-5-8-23(9-6-18(26)30-23)22(16,2)12-17-24(19,21)29-17/h10,15-17,19H,4-9,11-12H2,1-3H3/t15-,16+,17-,19+,21+,22+,23-,24-/m1/s1

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00700
Curator's Comment: Description was created based on several sources, including https://www.drugs.com/cdi/eplerenone.html

Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. Used for improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mineralocorticoid receptor 53 Target ID: CHEMBL1994 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20672820	Antagonist 2778		122.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hypertension 567 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021437s006lbl.pdf	Primary		Approved 8429	INSPRA Approved Use INSPRA is an aldosterone antagonist indicated for: Improving survival of stable patients with LV systolic dysfunction (LVEF ≤40%) and CHF after an acute myocardial infarction. Hypertension, alone or combined with other agents. Launch Date 2002

C_max

Value	Dose	Co-administered	Analyte	Population
2.49 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/14570778	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		EPLERENONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
18.4 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/14570778	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		EPLERENONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.01 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/14570778	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		EPLERENONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
38.2% EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/14570778	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		EPLERENONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
200 mg 2 times / day multiple, oral Highest studied dose Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12160194	unhealthy, 21-80 years n = 48 Health Status: unhealthy Condition: hypertension Age Group: 21-80 years Sex: M+F Population Size: 48 Sources: https://pubmed.ncbi.nlm.nih.gov/12160194	Other AEs: Arthralgia, Dizziness... Other AEs: Arthralgia (6%) Dizziness (6%) Leg cramps (6%) Infection respiratory (13%) Sinusitis (2%) Nausea (4%) Sources: https://pubmed.ncbi.nlm.nih.gov/12160194
400 mg 1 times / day multiple, oral Highest studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12160194	unhealthy, 21-80 years n = 56 Health Status: unhealthy Condition: hypertension Age Group: 21-80 years Sex: M+F Population Size: 56 Sources: https://pubmed.ncbi.nlm.nih.gov/12160194	Other AEs: Dizziness, Nausea... Other AEs: Dizziness (2%) Nausea (5%) Sources: https://pubmed.ncbi.nlm.nih.gov/12160194
50 mg 1 times / day multiple, oral Dose: 50 mg, 1 times / day Route: oral Route: multiple Dose: 50 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01237899	healthy n = 15 Health Status: healthy Population Size: 15 Sources: https://clinicaltrials.gov/ct2/show/NCT01237899	Other AEs: Palpitations, Diarrhoea... Other AEs: Palpitations (below serious, 1 patient) Diarrhoea (below serious, 1 patient) Fatigue (below serious, 2 patients) Vessel puncture site reaction (below serious, 1 patient) Fungal skin infection (below serious, 1 patient) Nasopharyngitis (below serious, 3 patients) Dizziness (below serious, 2 patients) Headache (below serious, 5 patients) Pollakiuria (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT01237899

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767 substrate 1037	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 P-gp 1461 CYP2E1 882	P-gp 1537	Cav1.2 4

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 18.0	no [IC50 >300 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 18.0	no [IC50 >300 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 18.0	no [IC50 >300 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 18.0	no [IC50 >300 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 45.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 18.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 18.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 41.0	weak

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 9, 10, 15	major	yes (co-administration study) Comment: coadministered with ketoconazole increased elperenone AUC by 5.5-fold and Cmax by 1.7-fold and with erythromycin increased AUC by 1.8-fold and Cmax 61% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 9, 10, 15
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 18, 34	no
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 10.0	yes	yes (co-administration study) Comment: coadminstration with fluconazole increased eplerenone AUC by 2.2-fold and Cmax by 1.4-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_BioPharmr_P1.pdf Page: 10.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
Cav1.2 49	inducer 27 Sources: https://pubmed.ncbi.nlm.nih.gov/21764470/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:31547	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:31547
MolPort	MolPort-003-986-216	https://www.molport.com/shop/molecule-link/MolPort-003-986-216
Selleck Chemicals	Eplerenone(Inspra)	http://www.selleckchem.com/products/Eplerenone(Inspra).html
ZINC	ZINC000003985982	http://zinc15.docking.org/substances/ZINC000003985982
eMolecules	29539569	https://www.emolecules.com/cgi-bin/more?vid=29539569
eMolecules	32234158	https://www.emolecules.com/cgi-bin/more?vid=32234158

PubMed

Title	Date	PubMed
[Efficacy of an aldosterone receptor blocker eplerenone in high risk survivors of acute myocardial infarction with signs of heart failure: results of EPHESUS].	2003	12974260
Aldosterone receptor antagonists for hypertension: what do they offer?	2003	12962513
Aldosterone antagonism in addition to angiotensin-converting enzyme inhibitors in heart failure.	2003 Apr	12783071
Hypertension, angiotensin II, aldosterone, and race.	2003 Apr 2	12679216
Aldosterone receptor antagonists in the treatment of heart failure.	2003 Aug	14502862
Primary aldosteronism - treatment options.	2003 Aug	12914736
Selective aldosterone blockade with eplerenone in patients with congestive heart failure.	2003 Aug	12882627
Aldosterone blockade and vascular calcification in hemodialysis patients.	2003 Aug 15	12935835
Eplerenone: a selective aldosterone blocker.	2003 Fall	12931252
Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension.	2003 Jul 1	12842242
Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure.	2003 Jul 11	12791709
Symptoms and the distress they cause: comparison of an aldosterone antagonist and a calcium channel blocking agent in patients with systolic hypertension.	2003 Jul 14	12860576
Eplerenone in patients with left ventricular dysfunction.	2003 Jul 3	12846224
Eplerenone in patients with left ventricular dysfunction.	2003 Jul 3	12846223
Eplerenone in patients with left ventricular dysfunction.	2003 Jul 3	12840098
[Anti-angiogenic effects of aldosterone antagonists in the fibrin chamber in rats].	2003 Jul-Aug	12945230
Hyperkalemia, congestive heart failure, and aldosterone receptor antagonism.	2003 Jul-Aug	12937359
Gateways to clinical trials.	2003 Jun	12851663
Late breaking heart failure trials from the 2003 ACC meeting: EPHESUS and COMPANION.	2003 Jun	12815564
Update of clinical trials from the American College of Cardiology 2003. EPHESUS, SPORTIF-III, ASCOT, COMPANION, UK-PACE and T-wave alternans.	2003 Jun	12798839
Aldosterone resurgens--letter from EPHESUS.	2003 Jun	12788830
Inhibition of platelet activation in congestive heart failure by aldosterone receptor antagonism and ACE inhibition.	2003 Jun	12783115
Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice.	2003 Jun	12775976
Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction.	2003 Jun 1	12798439
Eplerenone. Pharmacia.	2003 Mar	12744223
Aldosterone as a target in congestive heart failure.	2003 Mar	12693733
Aldosterone and aldosterone antagonism in cardiovascular disease: focus on eplerenone (Inspra).	2003 Mar-Apr	12713678
Aldosterone receptor blockade: a therapy resurrected.	2003 Mar-Apr	12713674
Aldosterone antagonism and hypertension.	2003 May	12769246
More hope for heart failure. Findings suggest expanded use of aldosterone-blockers.	2003 May	12739453
New developments in the pharmacological treatment of chronic heart failure.	2003 May	12720487
Effects of the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic hypertension.	2003 May	12682082
Eplerenone (Inspra).	2003 May 12	12736599
Eplerenone: cardiovascular protection.	2003 May 20	12756192
Aldosterone blockade in patients with acute myocardial infarction.	2003 May 27	12777314
Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans.	2003 Nov	14570778
Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy?	2003 Nov	14551174
Ask the doctor. I am a 50-year-old man with congestive heart failure. My doctor has me on all the usual drugs, and a couple of years ago added spironolactone. I did okay with it for a while, but then began to notice that my breasts were getting bigger and began to hurt. My doctor agreed that I should stop taking spironolactone, but I wonder if I am missing out on something.	2003 Oct	14576040
Aldosterone receptor blockade and the role of eplerenone: evolving perspectives.	2003 Oct	13679471
RAAS escape: a real clinical entity that may be important in the progression of cardiovascular and renal disease.	2003 Oct	12948434
Two better than one.	2003 Oct 14	14557352
Aldosterone blockade in patients with systolic left ventricular dysfunction.	2003 Oct 14	14557343
Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study.	2003 Oct 14	14517164
Long-term safety and efficacy of the selective aldosterone blocker eplerenone in patients with essential hypertension.	2003 Sep	14604739
Gateways to clinical trials.	2003 Sep	14571286
Should the aldosterone-receptor antagonist - eplerenone - be used after acute myocardial infarction with left ventricular dysfunction?	2003 Sep	12943490
New developments in the management of hypertension.	2003 Sep 1	13678132
Aldosterone blockade after myocardial infarction.	2003 Sep 2	12952808
Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure.	2003 Sep-Oct	14503934
Adjunctive treatment with eplerenone reduced morbidity and mortality in acute myocardial infarction.	2003 Sep-Oct	12954024

Patents

Sample Use Guides

In Vivo Use Guide

Congestive heart failure post-myocardial infarction: Initial dosage: 25 mg orally once daily. Dosage should titrated to the target dose of 50 mg once daily preferably within 4 weeks. Usual Adult Dose for Hypertension 50 mg orally once daily. Patients with an inadequate blood pressure response should be increased to 50 mg twice a day.

Route of Administration: Oral

In Vitro Use Guide

Eplerenone (10uM) significantly decreased corticosterone- (0.81 fold compared to treatment with corticosterone alone) and 11-DHC-driven (0.64 fold compared to treatment with 11-DHC alone) mouse VSMC calcification

Name

Type

Language

EPLERENONE

Official Name

English

EPLERENONE [JAN]

Common Name

English

EPLERENONE [ORANGE BOOK]

Common Name

English

INSPRA

Brand Name

English

EPLERENONE [MI]

Common Name

English

eplerenone [INN]

Common Name

English

EPLERENONE [EP MONOGRAPH]

Common Name

English

EPLERENONE [VANDF]

Common Name

English

SC-66110

Code

English

PREGN-4-ENE-7,21-DICARBOXYLIC ACID, 9,11-EPOXY-17-HYDROXY-3-OXO-, G-LACTONE, METHYL ESTER, (7.ALPHA.,11.ALPHA.,17.ALPHA)-

Common Name

English

9,11α-Epoxy-17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid, γ-lactone, methyl ester

Common Name

English

Eplerenone [WHO-DD]

Common Name

English

SC-6611O

Code

English

EPLERENONE [MART.]

Common Name

English

EPLERENONE [USP-RS]

Common Name

English

EPLERENONE [HSDB]

Common Name

English

EPLERENONE [USAN]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QC03DA04