BEMPEDOIC ACID

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H36O5
Molecular Weight	344.4861
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)(CCCCCC(O)CCCCCC(C)(C)C(O)=O)C(O)=O

InChI

InChIKey=HYHMLYSLQUKXKP-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: http://www.esperion.com/development/bempedoic-acid/ | https://www.ncbi.nlm.nih.gov/pubmed/27663902

Bempedoic acid (also known as ETC-1002) is a novel investigational drug being developed for the treatment of dyslipidemia, hypercholesterolemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid β-oxidation. Investigations into the mechanism of action revealed that bempedoic acid-free acid activates AMP-activated protein kinase in a Ca(2+)/calmodulin-dependent kinase β-independent and liver kinase β-1-dependent manner, without detectable changes in adenylate energy charge. In the liver, bempedoic acid is also converted to a coenzyme A (CoA) derivative (ETC-1002-CoA )which directly inhibits ATP citrate lyase (ACL), a key enzyme that supplies a substrate for cholesterol and fatty acid synthesis in the liver. Inhibition of ACL by ETC-1002-CoA results in reduced cholesterol synthesis and upregulation of LDL receptor activity in the liver. This promotes the removal of LDL-C from the blood.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ATP-citrate synthase 6 Target ID: P53396 Gene ID: 47.0 Gene Symbol: ACLY Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/28064554	Inhibitor 8297
AMPK alpha1/alpha2 1 Target ID: CHEMBL3038454 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23118444	Activator 1430

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hypercholesterolemia 47 Sources: https://clinicaltrials.gov/ct2/show/NCT02666664	Primary		Phase III 656	Unknown Approved Use Unknown
Dyslipidemia 30 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27676196	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
20.6 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		BEMPEDOIC ACID plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
289 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		BEMPEDOIC ACID plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
21 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		BEMPEDOIC ACID plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
180 mg 1 times / day steady, oral Recommended Dose: 180 mg, 1 times / day Route: oral Route: steady Dose: 180 mg, 1 times / day Co-administed with:: Statin Other Lipid Lowering Therapies Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf	unhealthy, 65.4 years n = 2009 Health Status: unhealthy Condition: atherosclerotic cardiovascular disease & heterozygous familial hypercholesterolemia Age Group: 65.4 years Sex: M+F Population Size: 2009 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf	Disc. AE: Muscle spasms, Pain in extremity... Other AEs: Upper respiratory tract infection, Muscle spasms... AEs leading to discontinuation/dose reduction: Muscle spasms (0.5%) Pain in extremity (0.3%) Diarrhea (0.4%) Other AEs: Upper respiratory tract infection (4.5%) Muscle spasms (3.6%) Hyperuricemia (3.5%) Back pain (3.3%) Abdominal pain (3.1%) Bronchitis (3%) Pain in extremity (3%) Anemia (2.8%) Elevated liver enzymes (2.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf
180 mg 1 times / day steady, oral Recommended Dose: 180 mg, 1 times / day Route: oral Route: steady Dose: 180 mg, 1 times / day Co-administed with:: ezetimibe(10 mg/day; oral; 4 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/29910030/	unhealthy, adults n = 181 Health Status: unhealthy Condition: hypercholesterolemia Age Group: adults Sex: M+F Population Size: 181 Sources: https://pubmed.ncbi.nlm.nih.gov/29910030/	Disc. AE: Muscle spasms, Myalgia... Other AEs: Blood uric acid increased, Headache... AEs leading to discontinuation/dose reduction: Muscle spasms (0.55%) Myalgia (0.55%) Pain in extremity (0.55%) Other AEs: Blood uric acid increased (grade 1-2, 7.7%) Headache (grade 1-2, 4.4%) Urinary tract infection (grade 1-2, 2.8%) Liver function test increased (grade 1-2, 3.9%) Nausea (grade 1-2, 2.8%) Sinusitis (grade 1-2, 2.8%) Nasopharyngitis (grade 1-2, 2.2%) Glomerular filtration rate decreased (grade 1-2, 2.2%) Diabetes mellitus (grade 1-2, 1.1%) Muscle spasms (grade 1-2, 3.3%) Myalgia (grade 1-2, 1.7%) Transaminases increased (grade 1-2, 3.9%) Muscular weakness (grade 1-2, 0.6%) Pain in extremity (grade 1-2, 0.6%) Sources: https://pubmed.ncbi.nlm.nih.gov/29910030/
180 mg 1 times / day steady, oral Recommended Dose: 180 mg, 1 times / day Route: oral Route: steady Dose: 180 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30922146/	unhealthy, adults n = 234 Health Status: unhealthy Condition: hypercholesterolemia Age Group: adults Sex: M+F Population Size: 234 Sources: https://pubmed.ncbi.nlm.nih.gov/30922146/	Disc. AE: Myalgia... Other AEs: Arthralgia, Hypertension... AEs leading to discontinuation/dose reduction: Myalgia (3.4%) Other AEs: Arthralgia (grade 1-2, 6%) Hypertension (grade 1-2, 4.3%) Fatigue (grade 1-2, 3.4%) Urinary tract infection (grade 1-2, 3.4%) Back pain (grade 1-2, 3%) Dizziness (grade 1-2, 3%) Bronchitis (grade 1-2, 2.6%) Blood creatine phosphokinase increased (grade 1-2, 2.1%) Dyspepsia (grade 1-2, 2.1%) Pain in extremity (grade 1-2, 5.6%) Myalgia (grade 1-2, 4.7%) Muscle spasms (grade 1-2, 4.3%) Muscular weakness (grade 1-2, 0.4%) Gout (grade 1-2, 1.7%) Transaminases increased (grade 1-2, 1.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/30922146/
180 mg 1 times / day steady, oral Recommended Dose: 180 mg, 1 times / day Route: oral Route: steady Dose: 180 mg, 1 times / day Co-administed with:: Statin Other Lipid Lowering Therapies Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf	unhealthy, adults n = 2009 Health Status: unhealthy Condition: atherosclerotic cardiovascular disease & heterozygous familial hypercholesterolemia Age Group: adults Sex: M+F Population Size: 2009 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf	Other AEs: Tendon rupture, Gout... Other AEs: Tendon rupture (0.5%) Gout (1.5%) Benign prostatic hyperplasia (1.3%) Atrial fibrillation (1.7%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf
220 mg 1 times / day multiple, oral Highest studied dose Dose: 220 mg, 1 times / day Route: oral Route: multiple Dose: 220 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf	healthy Health Status: healthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf
240 mg 1 times / day steady, oral Highest studied dose Dose: 240 mg, 1 times / day Route: oral Route: steady Dose: 240 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf	unhealthy n = 36 Health Status: unhealthy Condition: hypercholesterolemia Population Size: 36 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf
250 mg 1 times / day single, oral Highest studied dose Dose: 250 mg, 1 times / day Route: oral Route: single Dose: 250 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf	healthy n = 9 Health Status: healthy Population Size: 9 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	ACSVL1 1

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
ACSVL1 1	substrate 3367 Sources: https://www.tandfonline.com/doi/abs/10.1080/14656566.2019.1583209 Page: -	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:149601	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:149601
ChemicalBook	CB73034632	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB73034632
MolPort	MolPort-042-682-633	https://www.molport.com/shop/molecule-link/MolPort-042-682-633
ZINC	ZINC000003948738	http://zinc15.docking.org/substances/ZINC000003948738

PubMed

Title	Date	PubMed
Cloning and expression of a human ATP-citrate lyase cDNA.	1992 Mar 1	1371749

Patents

Sample Use Guides

In Vivo Use Guide

ETC-1002 (BEMPEDOIC ACID) 180 mg tablets taken orally, once per day.

Route of Administration: Oral

In Vitro Use Guide

Consistent with ETC-1002-induced AMPK activation observed in rat liver, HepG2 cells treated with ETC-1002 (100 uM) revealed a sustained and concentration-dependent increase in AMPK (T172) and ACC (S79) phosphorylation comparable to the AMPK-activating effect of metformin (1,000 μM). To further characterize the mechanism leading to AMPK activation by ETC-1002, HepG2 cells were pretreated with STO-609, an AMPK kinase Ca2+/calmodulin-dependent kinase β (CaMKKβ)-specific inhibitor. STO-609 did not significantly reduce AMPK or ACC phosphorylation in ETC-1002- or metformin-treated cells, indicating that AMPK activation is not dependent on intracellular Ca2+ signaling. Intriguingly, while the ATP analog and AMPK inhibitor, compound C, significantly reduced AMPK and ACC phosphorylation by metformin, it did not inhibit ETC-1002-dependent AMPK activation. To determine whether ETC-1002-dependent AMPK activation is associated with reductions in AEC, intracellular ATP, ADP, and AMP concentrations were measured in HepG2 cells treated with vehicle, rotenone (10 μM), or ETC-1002 (100 μM). Treatment with rotenone (complex I inhibitor) resulted in increased AMP and ADP levels and in reduced ATP levels and AEC compared with vehicle treatment, while ETC-1002 had no effect. These data suggest that the activation of the AMPK pathway by ETC-1002 may be independent of reductions in energy production.

Name

Type

Language

BEMPEDOIC ACID

Official Name

English

PENTADECANEDIOIC ACID, 8-HYDROXY-2,2,14,14-TETRAMETHYL-

Common Name

English

BEMPEDOIC ACID [ORANGE BOOK]

Common Name

English

8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid

Systematic Name

English

NEXLIZET COMPONENT BEMPEDOIC ACID

Brand Name

English

ETC1002

Code

English

NEXLETOL

Brand Name

English

ETC-1002

Code

English

ESP-55016

Code

English

BEMPEDOIC ACID [USAN]

Common Name

English

Bempedoic acid [WHO-DD]

Common Name

English

BEMPEDOIC ACID [JAN]

Common Name

English

BEMPEDOIC ACID COMPONENT OF NEXLIZET

Brand Name

English

bempedoic acid [INN]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

812621