DrugBank: Eplerenone (DB00700)

targets (1) enzymes (4)

Identification

Name

Eplerenone

Accession Number

DB00700 (APRD00707)

Type

small molecule

Groups

approved

Description

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.

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Epoxymexrenone

Brand names

INSPRA

Brand name mixtures

Not Available

Categories

Antihypertensive Agents
Aldosterone Antagonists

CAS number

107724-20-9

Weight

Average: 414.4914
Monoisotopic: 414.204238692

Chemical Formula

C₂₄H₃₀O₆

InChI Key

InChIKey=JUKPWJGBANNWMW-MKKQDWMASA-N

InChI

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

Plain Text

IUPAC Name

methyl (1'R,2R,2'S,9'R,11'S,15'S)-2',15'-dimethyl-5,5'-dioxo-18'-oxaspiro[oxolane-2,14'-pentacyclo[8.8.0.0^{1,17}.0^{2,7}.0^{11,15}]octadecan]-6'-ene-9'-carboxylate

SMILES

[H][C@@]12CC[C@@]3(CCC(=O)O3)[C@@]1(C)CC1O[C@@]11C2[C@@H](CC2=CC(=O)CC[C@]12C)C(=O)OC

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Steroids and Steroid Derivatives

Substructures

Steroids and Steroid Derivatives
Carboxylic Acids and Derivatives
Alkanes and Alkenes
Acetates
Lactones
Ethers
Heterocyclic compounds
Furans
Cyclohexenes and Derivatives
Epoxides
Ketones

Pharmacology

Indication

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.

Pharmacodynamics

Mechanism of action

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.

Absorption

The absolute bioavailability of eplerenone is unknown.

Volume of distribution

43 to 90 L

Protein binding

50%

Metabolism

Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma.

Route of elimination

Not Available

Half life

4-6 hours

Clearance

Apparent plasma cl=10 L/hr

Toxicity

The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia. However, no cases of human overdosage with eplerenone have been reported.

Affected organisms

Humans and other mammals

Pathways

Pathway	Name	SMPDB ID
	Eplerenone Pathway	SMP00135

Pharmacoeconomics

Manufacturers

Apotex inc
Sandoz inc
Gd searle llc

Packagers

Dosage forms

Form	Route	Strength
Tablet, film coated	Oral

Prices

Unit description	Cost	Unit
Inspra 25 mg tablet	4.87 USD	tablet
Inspra 50 mg tablet	4.87 USD	tablet
Eplerenone 25 mg tablet	4.18 USD	tablet
Eplerenone 50 mg tablet	4.18 USD	tablet

Patents

Country	Patent Number	Approved	Expires
United States	6863902	2000-10-10	2020-10-10
United States	6410524	1999-11-05	2019-11-05

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
water solubility	Slightly soluble	PhysProp
logP	1.3	PhysProp

Predicted Properties

Property	Value	Source
water solubility	9.03e-03 g/l	ALOGPS
logP	1.67	ALOGPS
logP	2.33	ChemAxon Molconvert
logS	-4.66	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	4	ChemAxon Molconvert
hydrogen donor count	0	ChemAxon Molconvert
polar surface area	82.20	ChemAxon Molconvert
rotatable bond count	2	ChemAxon Molconvert
refractivity	106.68	ChemAxon Molconvert
polarizability	43.82	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Drug	D01115
KEGG Compound	C12512
PubChem Compound	150310
PubChem Substance	46509053
ChemSpider	132492
ChEBI	31547
ChEMBL	31547
Therapeutic Targets Database	DAP000085
PharmGKB	PA10071
Drug Product Database	0
RxList	http://www.rxlist.com/cgi/generic/inspra.htm
Drugs.com	http://www.drugs.com/cdi/eplerenone.html
PDRhealth	http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ins1681.shtml
Wikipedia	http://en.wikipedia.org/wiki/Eplerenone

ATC Codes

C03DA04

AHFS Codes

Not Available

PDB Entries

Not Available

FDA label

show (135.9 KB)

MSDS

show (68.2 KB)

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. Mineralocorticoid receptor Pharmacological action: yes Actions: antagonist Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels Organism class: human UniProt ID: P08235 Gene: NR3C2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Moore TD, Nawarskas JJ, Anderson JR: Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis. 2003 Sep-Oct;5(5):354-63. Pubmed Fraccarollo D, Galuppo P, Hildemann S, Christ M, Ertl G, Bauersachs J: Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol. 2003 Nov 5;42(9):1666-73. Pubmed Rogerson FM, Yao Y, Smith BJ, Fuller PJ: Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor. Clin Exp Pharmacol Physiol. 2004 Oct;31(10):704-9. Pubmed Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Targets

1. Mineralocorticoid receptor

Pharmacological action: yes
Actions: antagonist

Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels

Organism class: human
UniProt ID: P08235 Link_out

Gene: NR3C2 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Moore TD, Nawarskas JJ, Anderson JR: Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis. 2003 Sep-Oct;5(5):354-63. Pubmed
Fraccarollo D, Galuppo P, Hildemann S, Christ M, Ertl G, Bauersachs J: Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol. 2003 Nov 5;42(9):1666-73. Pubmed
Rogerson FM, Yao Y, Smith BJ, Fuller PJ: Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor. Clin Exp Pharmacol Physiol. 2004 Oct;31(10):704-9. Pubmed
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes
1. Cytochrome P450 3A4 Actions: substrate Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide UniProt ID: P08684 Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed 2. Cytochrome P450 3A5 Actions: substrate Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics UniProt ID: P20815 Gene: CYP3A5 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010. 3. Cytochrome P450 3A7 Actions: substrate Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics UniProt ID: P24462 Gene: CYP3A7 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010. 4. Cytochrome P450 11B2, mitochondrial Actions: inhibitor Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone UniProt ID: P19099 Gene: CYP11B2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out

Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A5

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out

Gene: CYP3A5 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A7

Actions: substrate

UniProt ID: P24462 Link_out

Gene: CYP3A7 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 11B2, mitochondrial

Actions: inhibitor

Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone

UniProt ID: P19099 Link_out

Gene: CYP11B2 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:05

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.