Identification

Name
Bempedoic acid
Accession Number
DB11936
Description

High levels of LDL cholesterol (LDL-C) are a major risk factor for cardiovascular events. Caused by genetic mutations or lifestyle factors, hypercholesterolemia can significantly reduce quality of life and increase the risk of mortality from cardiovascular disease.9 About 1 in 4 patients, or 15 million Americans with elevated LDL-C, are insufficiently managed with maximally tolerated statin therapy alone, requiring additional treatment for hypercholesterolemia.12

Bempedoic acid is first-in-class adenosine triphosphate-citrate lyase (ACL) inhibitor used once a day for reducing LDL cholesterol levels in statin-refractory patients.6,7 It was developed by Esperion Therapeutics Inc. and approved by the FDA on February 21, 2020. A combination product of bempedoic acid and ezetimibe was approved on February 26, 2020 for increased control of LDL cholesterol levels in patients experiencing refractory elevations despite previous statin treatment.6,8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 344.492
Monoisotopic: 344.256274259
Chemical Formula
C19H36O5
Synonyms
  • Bempedoic acid
External IDs
  • ESP 55016
  • ESP-55016
  • ETC 1002
  • ETC-1002
  • ETC1002

Pharmacology

Indication

Bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or existing atherosclerotic cardiovascular disease that warrants additional lowering of LDL-C.6

The combination of bempedoic and ezetimibe is also indicated with diet management and maximally tolerated statin therapy to treat elevated LDL-C levels in adults with heterozygous familial hypercholesterolemia or existing atherosclerotic cardiovascular disease who require further lowering of LDL-C.8

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Bempedoic acid inhibits the synthesis of cholesterol in the liver, reducing LDL-C levels. This reduces the development of atherosclerotic plaques that may increase the risk of cardiovascular events.1,4 Earlier clinical trials studying the effects of bempedoic acid showed a dose‐dependent reduction of LDL‐C levels in addition to decreased LDL particle number, and reduced levels of apolipoprotein B, non–HDL cholesterol, and high‐sensitivity C‐reactive protein.2

Due to its unique mechanism of action, bempedoic acid is not associated with myositis, an adverse effect that frequently accompanies statin therapy.2

More recent trials have supported that this drug significantly decreases LDL-C levels after 12 weeks of therapy and provides additional lowering of LDL-C when combined with ezetimibe and statin therapy.5,2 The effects of bempedoic acid on mortality are currently unknown.4,6

Mechanism of action

Normally, LDL cholesterol is produced in the liver and circulates in the blood. When the blood becomes saturated, excess LDL deposits in blood vessels including the coronary arteries, increasing the risk of cardiovascular events.9,11

Bempedoic acid is a prodrug that requires activation in the liver. The very-long-chain acyl-CoA synthetase-1 (ACSVL1) enzyme is responsible for its activation to ETC-1002-CoA, the pharmacologically active metabolite. ATP lyase (also known as ATP synthase) plays an important part of cholesterol synthesis. BETC-1002-CoA directly inhibits this enzyme after the parent drug is activated in the liver by coenzyme A (CoA).5,6

This inhibition leads to upregulation of the LDL cholesterol receptor, reducing serum LDL-C via increased uptake and LDL clearance in the liver. By the above mechanisms, bempedoic acid causes a total decrease of circulating LDL-C that normally damages blood vessels and leads to atherosclerosis.1,3,6 Lastly, ETC-1002 activates AMP-activated protein kinase (AMPK) in rodents, which inhibits the synthesis of cholesterol via the inhibition of HMG-CoA reductase. The relevance of this to humans is unknown.2

TargetActionsOrganism
AATP-citrate synthase
inhibitor
Humans
Absorption

Bempedoic acid is rapidly absorbed in the small intestine.1,2 The Tmax of the 180mg tablet is estimated at 3.5 hours.6

Volume of distribution

The apparent volume of distribution of bempedoic acid is about 18L.6

Protein binding

The plasma protein binding of bempedoic acid and its metabolites is about 99%.6

Metabolism

The two main metabolites of bempedoic metabolism are ETC-1002-CoA3 and ESP15228. Bempedoic acid is primarily eliminated via the metabolism of its acyl glucuronide. This drug is reversibly converted to an active metabolite (ESP15228) based on observations during in vitro studies. Both compounds resulting from the metabolism of bempedoic acid are metabolized to become inactive glucuronide conjugates by the enzyme UGT2B7.6

Hover over products below to view reaction partners

Route of elimination

Bempedoic acid's conjugates are primarily eliminated via the urine (70%) and the feces (30%). A total of 5% of the unchanged drug is excreted in the urine and feces, combined.6

Half-life

The half-life of bempedoic acid ranges between 15 and 24 hours.1 Prescribing information indicates a clearance of 21 hours +/- 11 hours.6

Clearance

The clearance (CL/F) of bempedoic acid at steady state was estimated at 11.2 mL/min during clinical trials.6

Adverse Effects
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Toxicity

LD50 information for bempedoic acid is not readily available in the literature. In the case of an overdose with bempedoic acid, contact the local poison control center. To this date, there is no experience with bempedoic acid overdoses. Employ general supportive measures.6

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AmbrisentanThe excretion of Ambrisentan can be decreased when combined with Bempedoic acid.
AsunaprevirThe excretion of Asunaprevir can be decreased when combined with Bempedoic acid.
AtalurenThe excretion of Bempedoic acid can be decreased when combined with Ataluren.
AtazanavirThe excretion of Bempedoic acid can be decreased when combined with Atazanavir.
AtorvastatinThe excretion of Atorvastatin can be decreased when combined with Bempedoic acid.
AxitinibThe excretion of Axitinib can be decreased when combined with Bempedoic acid.
BaricitinibThe excretion of Bempedoic acid can be decreased when combined with Baricitinib.
Beclomethasone dipropionateThe excretion of Bempedoic acid can be decreased when combined with Beclomethasone dipropionate.
BenzylpenicillinThe excretion of Benzylpenicillin can be decreased when combined with Bempedoic acid.
BosentanThe excretion of Bosentan can be decreased when combined with Bempedoic acid.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take with or without food.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NexletolTablet, film coated180 mg/1OralEsperion Therapeutics, Inc.2020-03-06Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
NexlizetBempedoic acid (180 mg/1) + Ezetimibe (10 mg/1)Tablet, film coatedOralEsperion Therapeutics, Inc.2020-03-09Not applicableUS flag

Categories

ATC Codes
C10AX15 — Bempedoic acid
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as long-chain fatty acids. These are fatty acids with an aliphatic tail that contains between 13 and 21 carbon atoms.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Fatty acids and conjugates
Direct Parent
Long-chain fatty acids
Alternative Parents
Methyl-branched fatty acids / Hydroxy fatty acids / Dicarboxylic acids and derivatives / Secondary alcohols / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Alcohol / Aliphatic acyclic compound / Branched fatty acid / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Dicarboxylic acid or derivatives / Hydrocarbon derivative / Hydroxy fatty acid / Long-chain fatty acid
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
1EJ6Z6Q368
CAS number
738606-46-7
InChI Key
HYHMLYSLQUKXKP-UHFFFAOYSA-N
InChI
InChI=1S/C19H36O5/c1-18(2,16(21)22)13-9-5-7-11-15(20)12-8-6-10-14-19(3,4)17(23)24/h15,20H,5-14H2,1-4H3,(H,21,22)(H,23,24)
IUPAC Name
8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
SMILES
CC(C)(CCCCCC(O)CCCCCC(C)(C)C(O)=O)C(O)=O

References

Synthesis Reference

David M Paton. Bempedoic Acid: ATP-citrate lyase inhibitor.(2017). Drugs of the Future. 42(4):201-208

General References
  1. Saeed A, Ballantyne CM: Bempedoic Acid (ETC-1002): A Current Review. Cardiol Clin. 2018 May;36(2):257-264. doi: 10.1016/j.ccl.2017.12.007. Epub 2018 Feb 21. [PubMed:29609755]
  2. Bilen O, Ballantyne CM: Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61. doi: 10.1007/s11883-016-0611-4. [PubMed:27663902]
  3. Zagelbaum NK, Yandrapalli S, Nabors C, Frishman WH: Bempedoic Acid (ETC-1002): ATP Citrate Lyase Inhibitor: Review of a First-in-Class Medication with Potential Benefit in Statin-Refractory Cases. Cardiol Rev. 2019 Jan/Feb;27(1):49-56. doi: 10.1097/CRD.0000000000000218. [PubMed:29939848]
  4. Jia X, Virani SS: CLEAR Serenity Trial: More Clarity for the Future of Bempedoic Acid in Patients Unable to Take Statins? J Am Heart Assoc. 2019 Apr 2;8(7):e012352. doi: 10.1161/JAHA.119.012352. [PubMed:30922156]
  5. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM: Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022-1032. doi: 10.1056/NEJMoa1803917. [PubMed:30865796]
  6. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]
  7. Bempedoic acid: A novel agent (Esperion) [Link]
  8. FDA Approved Products: Nexlizet (bempedoic acid and ezetimibe) oral tablets [Link]
  9. NIH StatPearls: Cholesterol levels [Link]
  10. Biovision: Bempedoic acid MSDS [Link]
  11. The Role of Lipids and Lipoproteins in Atherosclerosis [Link]
  12. Global News Wire: Esperion-Announces FDA Approval of NEXLETOL bempedoic acid Tablet an Oral Once Daily Non Statin LDL Cholesterol Lowering Medicine [Link]
PubChem Compound
10472693
PubChem Substance
347828263
ChemSpider
8648104
RxNav
2282403
ChEMBL
CHEMBL3545313
ZINC
ZINC000003948738
Wikipedia
Bempedoic_acid
FDA label
Download (576 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentCardiovascular Heart Disease / Statin Adverse Reaction1
3CompletedTreatmentAtherosclerosis / High Cholesterol / Statin Adverse Reaction1
3CompletedTreatmentAtherosclerotic Cardiovascular Diseases / High Cholesterol3
3CompletedTreatmentAtherosclerotic Cardiovascular Diseases / High Cholesterol / Statin Adverse Reaction1
3CompletedTreatmentHyperlipidemias1
2CompletedTreatmentCholesterolemia / Diabetes / Type 2 Diabetes Mellitus1
2CompletedTreatmentDyslipidemia1
2CompletedTreatmentHigh Blood Pressure (Hypertension) / High Cholesterol1
2CompletedTreatmentHigh Cholesterol6
2CompletedTreatmentHyperlipidemias1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral180 mg/1
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7335799No2008-02-262025-12-03US flag
US9624152No2017-04-182023-12-23US flag
US8497301No2013-07-302023-12-23US flag
US9000041No2015-04-072023-12-23US flag
US10118881No2018-11-062023-12-23US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)87-92https://www.trc-canada.com/product-detail/?CatNum=B119700
Predicted Properties
PropertyValueSource
Water Solubility0.0211 mg/mLALOGPS
logP3.65ALOGPS
logP5.3ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)4.44ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area94.83 Å2ChemAxon
Rotatable Bond Count14ChemAxon
Refractivity93.97 m3·mol-1ChemAxon
Polarizability41.08 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, the latter serving as common substrate for de novo cholesterol and fatty acid synthesis.
Specific Function
Atp binding
Gene Name
ACLY
Uniprot ID
P53396
Uniprot Name
ATP-citrate synthase
Molecular Weight
120838.27 Da
References
  1. Saeed A, Ballantyne CM: Bempedoic Acid (ETC-1002): A Current Review. Cardiol Clin. 2018 May;36(2):257-264. doi: 10.1016/j.ccl.2017.12.007. Epub 2018 Feb 21. [PubMed:29609755]
  2. Bilen O, Ballantyne CM: Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61. doi: 10.1007/s11883-016-0611-4. [PubMed:27663902]
  3. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]
  4. Bempedoic acid: A novel agent (Esperion) [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
Curator comments
This enzyme converts bempedoic acid into its active metabolite.
General Function
Acyl CoA synthetase that activates long-chain and very long-chain fatty acids (VLCFAs) by catalyzing the formation of fatty acyl-CoA (PubMed:10198260, PubMed:10749848, PubMed:11980911). Can also activate branched-chain fatty acids such as phytanic acid and pristanic acid (PubMed:10198260). Does not activate C24 bile acids, cholate and chenodeoxycholate (PubMed:11980911). In vitro, activates 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate (THCA), the C27 precursor of cholic acid deriving from the de novo synthesis from cholesterol (PubMed:11980911). Exhibits long-chain fatty acids (LCFA) transport activity and plays an important role in hepatic fatty acid uptake (PubMed:20530735).
Specific Function
Acyl-coa ligase activity
Gene Name
SLC27A2
Uniprot ID
O14975
Uniprot Name
Very long-chain acyl-CoA synthetase
Molecular Weight
70311.685 Da
References
  1. Saeed A, Ballantyne CM: Bempedoic Acid (ETC-1002): A Current Review. Cardiol Clin. 2018 May;36(2):257-264. doi: 10.1016/j.ccl.2017.12.007. Epub 2018 Feb 21. [PubMed:29609755]
  2. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]
  3. Bempedoic acid: A novel agent (Esperion) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Atp binding
Specific Function
Activates acetate so that it can be used for lipid synthesis or for energy generation.
Gene Name
ACSS2
Uniprot ID
Q9NR19
Uniprot Name
Acetyl-coenzyme A synthetase, cytoplasmic
Molecular Weight
78579.11 Da
References
  1. Bilen O, Ballantyne CM: Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61. doi: 10.1007/s11883-016-0611-4. [PubMed:27663902]
  2. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Activator
Curator comments
This enzyme inhibition occurs in rats. Relevance to humans is unknown.
General Function
Stress-activated kinase involved in tolerance to glucose starvation. Induces cell-cell detachment by increasing F-actin conversion to G-actin. Expression is induced by CD95 or TNF-alpha, via NF-kappa-B. Protects cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95-activated tumor cells. Able to phosphorylate 'Ser-464' of LATS1.
Specific Function
Atp binding
Gene Name
NUAK2
Uniprot ID
Q9H093
Uniprot Name
NUAK family SNF1-like kinase 2
Molecular Weight
69611.485 Da
References
  1. Bilen O, Ballantyne CM: Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61. doi: 10.1007/s11883-016-0611-4. [PubMed:27663902]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Weak inhibition.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Weak inhibition.
General Function
Organic anion transmembrane transporter activity
Specific Function
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocyte...
Gene Name
ABCC3
Uniprot ID
O15438
Uniprot Name
Canalicular multispecific organic anion transporter 2
Molecular Weight
169341.14 Da
References
  1. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Weak inhibition.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Products: Nexletol (bempedoic acid) oral tablets [Link]

Drug created on October 20, 2016 15:02 / Updated on June 12, 2020 10:53

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