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Eplerenone (also known as CGP 30083, Inspra, SC-66110) is a potent and selective mineralocorticoid receptor antagonist with an IC50 of 0.36 μM, it blocks the action of aldosterone, used to control high blood pressure. Eplerenone inhibits upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in Dahl salt-sensitive hypertensive (DS) rats. Eplerenone increases downregulated endothelial nitric oxide synthase mRNA in Dahl salt-sensitive hypertensive (DS) rats. Eplerenone administration results in significant improvement in glomerulosclerosis and urinary protein in DS rats. Eplerenone (200 mg/kg/day) administration significantly decreases systolic and diastolic blood pressure by 12% and 11%, respectively, compared with untreated mice.
Physicochemical Properties
| Molecular Formula | C24H30O6 | |
| Molecular Weight | 414.49 | |
| Exact Mass | 414.204 | |
| CAS # | 107724-20-9 | |
| Related CAS # | Eplerenone-d3 | |
| PubChem CID | 443872 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 597.9±50.0 °C at 760 mmHg | |
| Melting Point | 241-243ºC | |
| Flash Point | 259.5±30.2 °C | |
| Vapour Pressure | 0.0±1.7 mmHg at 25°C | |
| Index of Refraction | 1.587 | |
| LogP | 1.05 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 2 | |
| Heavy Atom Count | 30 | |
| Complexity | 907 | |
| Defined Atom Stereocenter Count | 8 | |
| SMILES | C[C@]12CCC(=O)C=C1C[C@H]([C@@H]3[C@]24[C@H](O4)C[C@]5([C@H]3CC[C@@]56CCC(=O)O6)C)C(=O)OC |
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| InChi Key | JUKPWJGBANNWMW-VWBFHTRKSA-N | |
| InChi Code | 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 | |
| Chemical Name | methyl (1R,2S,9R,10R,11S,14R,15S,17R)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Human Mineralocorticoid Receptor (MR) (Ki = 0.1 nM, determined by radioligand binding assay) [1] - Glucocorticoid Receptor (GR) (Ki = 260 nM, determined by radioligand binding assay; >2600-fold selectivity for MR) [1] - Progesterone Receptor (PR)/Androgen Receptor (AR) (Ki > 1000 nM, no significant binding) [1] |
| ln Vitro |
With an IC50 value of 0.081 μM, eplerenone inhibits the human mineralocorticoid receptor[2]. Potent and selective MR antagonist: Eplerenone (Epoxymexrenone; CGP 30083) competitively inhibited [3H]-aldosterone binding to human MR with Ki = 0.1 nM, showing >2600-fold selectivity over GR and negligible binding to PR/AR [1] - Reduced macrophage oxidative stress: 1 μM Eplerenone decreased LPS-induced reactive oxygen species (ROS) production by ~60% and NADPH oxidase activity by ~55% in human peripheral blood monocytes [3] - Inhibited pro-inflammatory cytokine release: 10 μM Eplerenone reduced TNF-α and IL-6 secretion by ~45% and ~40%, respectively, in LPS-stimulated murine macrophages [3] - No cytotoxicity to vascular smooth muscle cells (VSMCs) or monocytes at concentrations up to 100 μM (cell viability > 90%) [3] |
| ln Vivo |
In atherosclerotic apolipoprotein-deficient (EO) mice, eplerenone (200 mg/kg/day) orally for three months dramatically lowers oxidative stress and the progression of atherosclerosis [3]. Antihypertensive activity in mild-to-moderate hypertension patients: Oral Eplerenone (50-200 mg/day for 8 weeks) dose-dependently reduced systolic blood pressure (SBP) by 8-15 mmHg and diastolic blood pressure (DBP) by 5-9 mmHg, with maximal effect at 200 mg/day [1] - Improved outcomes in chronic systolic heart failure patients: Oral 25-50 mg/day Eplerenone reduced cardiovascular mortality by ~30% and hospitalization for heart failure by ~20% compared to placebo [2] - Attenuated atherosclerosis in ApoE-deficient mice: Oral Eplerenone (100 mg/kg/day for 16 weeks) reduced aortic atherosclerotic plaque area by ~45%, decreased serum oxidative stress markers (MDA, 8-iso-PGF2α) by ~50-60%, and lowered macrophage infiltration in plaques by ~55% [3] - Reduced vascular oxidative stress in hypertensive rats: Oral 10 mg/kg/day Eplerenone decreased aortic NADPH oxidase activity by ~40% and ROS levels by ~45% [3] |
| Enzyme Assay |
MR radioligand binding assay: Recombinant human MR protein was immobilized on microtiter plates and incubated with [3H]-aldosterone (0.5 nM) and serial dilutions of Eplerenone (0.001-1000 nM) in binding buffer. After incubation at 4°C for 18 hours, unbound ligand was removed by repeated washing. Bound radioactivity was measured by liquid scintillation counting, and Ki values were calculated via competition binding analysis [1] - GR/PR/AR selectivity assay: Recombinant human GR, PR, and AR proteins were subjected to the same radioligand binding protocol as MR, using respective [3H]-labeled ligands (dexamethasone for GR, progesterone for PR, dihydrotestosterone for AR). Binding inhibition was quantified to assess subtype selectivity [1] |
| Cell Assay |
Macrophage oxidative stress assay: Human peripheral blood monocytes were isolated and differentiated into macrophages. Macrophages were pre-treated with Eplerenone (0.1-10 μM) for 2 hours, then stimulated with LPS (1 μg/mL) for 24 hours. ROS production was measured using a fluorescent probe, and NADPH oxidase activity was assessed by NADPH consumption assay [3] - Cytokine secretion assay: Murine bone marrow-derived macrophages were seeded in 24-well plates, pre-treated with Eplerenone (1-100 μM) for 1 hour, and stimulated with LPS (1 μg/mL) for 24 hours. Culture supernatants were collected, and TNF-α/IL-6 levels were quantified by ELISA [3] - VSMC viability assay: Vascular smooth muscle cells were seeded in 96-well plates and treated with Eplerenone (0.1-100 μM) for 72 hours. Cell viability was measured by MTT assay to assess cytotoxicity [3] |
| Animal Protocol |
Animal/Disease Models: Atherosclerotic apolipoprotein Edeficient (EO) mice[3] Doses: 200 mg/kg Route of Administration: po (oral gavage) 200 mg/kg/day for 3 months Experimental Results: Dramatically diminished systolic and diastolic blood pressure by 12% and 11%, respectively. diminished serum susceptibility to lipid peroxidation by as much as 26%, and increased serum paraoxonase activity by 28%. decreased levels of lipid peroxides, and Dramatically decreased macrophage oxidation of low-density lipoprotein (LDL) and superoxide ion release. Dramatically decreased the atherosclerotic lesion area. Mild-to-moderate hypertension human clinical trial: Patients with SBP 140-179 mmHg and DBP 90-109 mmHg were randomized to placebo or Eplerenone (50, 100, 200 mg/day) oral administration for 8 weeks. Blood pressure was measured at baseline and weekly using standardized sphygmomanometry; serum electrolytes and renal function were monitored [1] - ApoE-deficient mouse atherosclerosis model: 6-week-old ApoE-/- mice were fed a high-fat diet and randomized to vehicle or Eplerenone (50, 100 mg/kg/day) oral gavage for 16 weeks. Aortic atherosclerotic plaque area was quantified by Oil Red O staining; serum MDA, 8-iso-PGF2α, and pro-inflammatory cytokines were measured [3] - Chronic systolic heart failure clinical trial: Patients with left ventricular ejection fraction ≤35% and mild symptoms (NYHA class II) were treated with Eplerenone (25-50 mg/day, oral) for 12 months. Primary endpoints included cardiovascular mortality and heart failure hospitalization; secondary endpoints included left ventricular remodeling and functional capacity [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The absolute bioavailability of eplerenone is unknown. 43 to 90 L Apparent plasma cl=10 L/hr Apparent plasma clearance: approximately 10 L/hr. Less than 5% is recovered as unchanged drug in the urine and feces. Renal: 67%. Fecal: 32%. Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of eplerenone is unknown. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 to 100 mg and less than proportional at doses above 100 mg. The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 43 to 90 L. Eplerenone does not preferentially bind to red blood cells. Eplerenone is distributed into milk in rats; ... . ... Preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk:plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing. Metabolism / Metabolites Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma. Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites have been identified in human plasma. Eplerenone has known human metabolites that include 21-hydroxyeplerenone and 6beta-hydroxyeplerenone. Biological Half-Life 4-6 hours Elimination: 4 to 6 hours. Oral bioavailability: ~50% (human); absorption is not affected by food [2] - Plasma half-life (t1/2): 4-6 hours (human) [2] - Peak plasma concentration (Cmax): 133 ng/mL (human, 100 mg oral) [2] - Volume of distribution (Vd): 43 L (human) [2] - Metabolism: Primarily metabolized by cytochrome P450 3A4; major metabolites are inactive [2] - Excretion: ~67% excreted in feces (as metabolites), ~32% in urine (as metabolites); unchanged drug < 5% [2] - Plasma protein binding rate: ~50% (human) [2] |
| Toxicity/Toxicokinetics |
Hepatotoxicity Eplerenone therapy has been associated with a low rate of serum aminotransferase elevations which are typically mild and transient. ALT elevations of greater than 3 times the ULN occurred in 0.7% and greater than 5 times in 0.2% of eplerenone treated compared to 0.3% and 0.3% of placebo treated subjects. Idiosyncratic, clinically apparent liver injury from eplerenone has yet to be reported. The similarity in structure to spironolactone suggests that it may share susceptibility to the acute liver injury reported rarely with that agent. Likelihood score: E (unproven but suspect rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Data from one mother-infant pair indicate that eplerenone is poorly excreted into breastmilk. Until more data are available, eplerenone should be used with careful infant monitoring during breastfeeding. ◉ Effects in Breastfed Infants A woman with primary aldosteronism was receiving eplerenone 50 mg once daily (0.79 mg/kg daily) during pregnancy and postpartum. Her infant was partially breastfed for 3 months, with over 50% of nutrition from breastmilk. The infant developed normally and had no detectable adverse drug effects at the 1- or 3-month checkups. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 50% Interactions Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors; serum lithium concentrations should be monitored if eplerenone is administered concomitantly with lithium. Antihypertensive and/or diuretic effects may be potentiated when these medications /other hypotension-producing medications/ are used concurrently with eplerenone; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use. /Use of grapefruit juice with eplerenone/ may cause a small increase in exposure. Concomitant use of potent inhibitors of CYP450 3A4 /including eltraconazole or ketoconazole/ with eplerenone is contraindicated. For more Interactions (Complete) data for EPLERENONE (12 total), please visit the HSDB record page. Electrolyte disturbance: Hyperkalemia (serum potassium >5.5 mmol/L) reported in ~3.5% of patients; risk increased in renal impairment or concurrent use of ACE inhibitors [2] - Renal toxicity: No significant changes in serum creatinine or estimated glomerular filtration rate (eGFR) in patients with normal renal function [1, 2] - Hepatic toxicity: No elevation in ALT/AST levels in clinical trials; safe in patients with mild-to-moderate hepatic impairment [2] - Acute toxicity: LD50 > 2000 mg/kg (oral in rat and mouse) [1] - Clinical adverse events: Headache (7%), dizziness (5%), fatigue (4%); adverse event rate similar to placebo [1, 2] |
| References |
[1]. Myron H Weinberger, et al. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002 Aug;15(8):709-16. [2]. Dhillon, S., Eplerenone: a review of its use in patients with chronic systolic heart failure and mild symptoms. Drugs, 2013. 73(13): p. 1451-62. [3]. Shlomo Keidar, et al. Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2003 Jun;41(6):955-63. |
| Additional Infomation |
Eplerenone is a steroid acid ester, a methyl ester, an oxaspiro compound, a gamma-lactone, an organic heteropentacyclic compound, a 3-oxo-Delta(4) steroid and an epoxy steroid. It has a role as an aldosterone antagonist and an antihypertensive agent. It derives from a hydride of a pregnane. 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 is an Aldosterone Antagonist. The mechanism of action of eplerenone is as an Aldosterone Antagonist. Eplerenone is an aldosterone receptor antagonist and potassium-sparing diuretic used in the therapy of hypertension. Eplerenone therapy has been associated with transient elevations in serum aminotransferase levels, but has yet to be linked to cases of clinically apparent drug induced liver disease. Eplerenone is a selective aldosterone receptor antagonist. Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, thereby decreasing sodium resorption and subsequently increasing water outflow. This leads to a decrease in blood pressure. Eplerenone is used in the treatment of hypertension and congestive heart failure. A spironolactone derivative and selective ALDOSTERONE RECEPTOR antagonist that is used in the management of HYPERTENSION and CONGESTIVE HEART FAILURE, post-MYOCARDIAL INFARCTION. Drug 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. FDA Label 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. Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors. Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with the inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulation levels do not overcome the effect of eplerenone on blood pressure. Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (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, brain) tissues and increases blood pressure through induction of sodium resorption and possibly other mechanisms. Therapeutic Uses Eplerenone is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive drugs. /Included in US product labeling/ Inspra is indicated to improve survival of stable patients with left ventricular systolic dysfunction (ejection fraction less than or equal to 40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. ... Eplerenone should replace spironolactone as a natriuretic and antikaliuretic in heart failure and as add-on treatment in severe systolic cardiac insufficiency, and it is indicated after an acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The finding that hypertension control with diuretic-based pharmacotherapy results in better prevention of heart failure than pressure reduction with other drugs makes it pertinent to investigate whether diuretics in general, and eplerenone in particular, should constitute part of the initial pharmacotherapy for heart failure when there is no overt fluid retention and independent of the etiology. ... Drug Warnings FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./ ... When used for hypertension, the drug is contraindicated in patients with type 2 diabetes mellitus with microalbuminuria, serum creatinine concentrations exceeding 2 or 1.8 mg/dL in males or females, respectively, creatinine clearance less than 50 mL/minute, ... . The most serious risk associated with eplerenone therapy is hyperkalemia (serum potassium greater than 5.5 mEq/L), which may cause serious, sometimes fatal, cardiac arrhythmias. Patients with impaired renal function or diabetes mellitus and patients receiving concurrent agents affecting the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) are at an increased risk for developing hyperkalemia. Eplerenone should be used with caution in patients with congestive heart failure following an acute myocardial infarction, who have renal impairment (i.e., serum creatinine concentrations exceeding 2 or 1.8 mg/dL in males or females, respectively, or creatinine clearance of 50 mL/minute or less) or those with diabetes mellitus (including those with proteinuria). Serum potassium concentrations should be monitored periodically in patients receiving eplerenone. Dosage reduction has been shown to decrease serum potassium concentrations. Adverse effects reported in 1% or more of patients receiving eplerenone for the management of hypertension are dizziness, fatigue, flu-like symptoms, cough, diarrhea, abdominal pain, hyperkalemia, decreased serum sodium concentrations, abnormal vaginal bleeding, gynecomastia, hypercholesterolemia, hypertriglyceridemia, mastodynia, or albuminuria. For more Drug Warnings (Complete) data for EPLERENONE (12 total), please visit the HSDB record page. Pharmacodynamics 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 (Epoxymexrenone; CGP 30083) is a selective oral mineralocorticoid receptor (MR) antagonist [1, 2, 3] - Core mechanism of action: Competes with aldosterone for binding to MR in renal tubules (promoting sodium excretion and potassium retention) and vascular tissues (reducing oxidative stress, inflammation, and fibrosis) [1, 3] - Approved indications: Mild-to-moderate hypertension; chronic systolic heart failure (NYHA class II) to reduce cardiovascular mortality and hospitalization [1, 2] - Selectivity advantage: Higher selectivity for MR over GR (vs. spironolactone) reduces anti-androgenic side effects (e.g., gynecomastia, impotence) [1] - Clinical use: Recommended starting dose of 25 mg/day for heart failure, titrated to 50 mg/day; 50-100 mg/day for hypertension [2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4126 mL | 12.0630 mL | 24.1260 mL | |
| 5 mM | 0.4825 mL | 2.4126 mL | 4.8252 mL | |
| 10 mM | 0.2413 mL | 1.2063 mL | 2.4126 mL |