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Details

Stereochemistry ABSOLUTE
Molecular Formula C32H43NO4
Molecular Weight 505.6881
Optical Activity UNSPECIFIED
Defined Stereocenters 7 / 7
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of BARDOXOLONE METHYL

SMILES

[H][C@@]12CC(C)(C)CC[C@@]1(CC[C@]3(C)[C@]2([H])C(=O)C=C4[C@@]3(C)CC[C@@]5([H])C(C)(C)C(=O)C(=C[C@]45C)C#N)C(=O)OC

InChI

InChIKey=WPTTVJLTNAWYAO-KPOXMGGZSA-N
InChI=1S/C32H43NO4/c1-27(2)11-13-32(26(36)37-8)14-12-31(7)24(20(32)17-27)21(34)15-23-29(5)16-19(18-33)25(35)28(3,4)22(29)9-10-30(23,31)6/h15-16,20,22,24H,9-14,17H2,1-8H3/t20-,22-,24-,29-,30+,31+,32-/m0/s1

HIDE SMILES / InChI

Molecular Formula C32H43NO4
Molecular Weight 505.6881
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 7 / 7
E/Z Centers 0
Optical Activity UNSPECIFIED

Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. Bardoxolone methyl directly blocks IKKbeta activity and thereby the NF-kappaB pathway by interacting with Cys-179 in the IKKbeta activation loop. Binding of bardoxolone methyl to Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) disrupts its critical cysteine residues, leading to the release of the nuclear factor erythroid 2-related factor 2 (Nrf2), which hinders its ubiquitination and finally leads to its stabilization and nuclear translocation. In the nucleus, Nrf2 activates the transcription of phase 2 response genes, leading to a coordinated antioxidant and anti-inflammatory response. In addition, it acts as an antagonist of the peroxisome proliferator-activated receptor gamma. Through Keap1/Nrf2 and nuclear factor-κB pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. This agent is generally well tolerated, but it may increase adverse cardiovascular events. Presently, it is being further tested for the treatment of patients with chronic kidney disease, cancer, and pulmonary arterial hypertension.

CNS Activity

Curator's Comment: Bardoxolone methyl is CNS active in animals. No human data available.

Approval Year

Doses

Doses

DosePopulationAdverse events​
900 mg 1 times / day multiple, oral
MTD
Dose: 900 mg, 1 times / day
Route: oral
Route: multiple
Dose: 900 mg, 1 times / day
Sources: Page: p.7
unhealthy, ADULT
n = 25
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 25
Sources: Page: p.7
1300 mg 1 times / day multiple, oral
Highest studied dose
Dose: 1300 mg, 1 times / day
Route: oral
Route: multiple
Dose: 1300 mg, 1 times / day
Sources: Page: p.7
unhealthy
n = 6
Health Status: unhealthy
Condition: cancer
Sex: M+F
Food Status: FASTED
Population Size: 6
Sources: Page: p.7
DLT: ALT increased...
Dose limiting toxicities:
ALT increased (grade 3, 33.3%)
Sources: Page: p.7
AEs

AEs

AESignificanceDosePopulation
ALT increased grade 3, 33.3%
DLT, Disc. AE
1300 mg 1 times / day multiple, oral
Highest studied dose
Dose: 1300 mg, 1 times / day
Route: oral
Route: multiple
Dose: 1300 mg, 1 times / day
Sources: Page: p.7
unhealthy
n = 6
Health Status: unhealthy
Condition: cancer
Sex: M+F
Food Status: FASTED
Population Size: 6
Sources: Page: p.7
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer



Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
inconclusive [IC50 21.1317 uM]
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma.
2000 Oct
The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice.
2007 Mar 15
Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles.
2008 Oct 14
Fatty acid synthesis is a therapeutic target in human liposarcoma.
2010 May
Tricyclic compounds containing nonenolizable cyano enones. A novel class of highly potent anti-inflammatory and cytoprotective agents.
2011 Mar 24
Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1.
2011 May
Protection against 2-chloroethyl ethyl sulfide (CEES)-induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway.
2011 Sep 1
Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway.
2014 Apr 6
Immunosuppressive potential of bardoxolone methyl using a modified murine local lymph node assay (LLNA).
2014 Aug
Chemical tuning enhances both potency toward nrf2 and in vitro therapeutic index of triterpenoids.
2014 Aug 1
Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet.
2016 Jan 5
Patents

Patents

Sample Use Guides

Single dose administration of 20, 60, and 80 mg bardoxolone methyl was safe and well-tolerated in healthy volunteers. In a Phase I trial in cancer patients, bardoxolone methyl was found to have a slow and saturable oral absorption, a relatively long terminal phase half-life (39 hours at 900 mg/day), nonlinearity (dose-dependent) at high doses (600-1,300 mg/day), and high interpatient variability. Phase 3 study of the long-term safety and tolerability of bardoxolone methyl in qualified patients with pulmonary hypertension: Bardoxolone methyl will be administered orally once daily at 10 mg until it becomes commercially available. Dose de-escalation (down to 5 mg) is permitted during the study, if indicated clinically.
Route of Administration: Oral
Bardoxolone methyl at concentrations of 25 to 100 nmol/L completely abrogated immune suppressive activity of myeloid-derived suppressor cells in vitro.
Substance Class Chemical
Created
by admin
on Fri Dec 15 16:15:46 UTC 2023
Edited
by admin
on Fri Dec 15 16:15:46 UTC 2023
Record UNII
CEG1Q6OGU1
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
BARDOXOLONE METHYL
USAN   WHO-DD  
USAN  
Official Name English
BARDOXOLONE METHYL ESTER [MI]
Common Name English
RTA-402
Code English
BARDOXOLONE METHYL [USAN]
Common Name English
Methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate
Common Name English
Bardoxolone methyl [WHO-DD]
Common Name English
CDDO-METHYL ESTER
Code English
NSC-713200
Code English
RTA402
Code English
BARDOXOLONE METHYL [JAN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C29574
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
EU-Orphan Drug EU/3/18/2019
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
FDA ORPHAN DRUG 687219
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
FDA ORPHAN DRUG 568016
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
NCI_THESAURUS C1323
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
Code System Code Type Description
NCI_THESAURUS
C98250
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
NSC
713200
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
PUBCHEM
400769
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
CAS
218600-53-4
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
USAN
TT-40
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
ChEMBL
CHEMBL1762621
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
WIKIPEDIA
BARDOXOLONE METHYL
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
FDA UNII
CEG1Q6OGU1
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
DRUG BANK
DB05983
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
MERCK INDEX
m2229
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY Merck Index
SMS_ID
300000010624
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
EPA CompTox
DTXSID5048764
Created by admin on Fri Dec 15 16:15:46 UTC 2023 , Edited by admin on Fri Dec 15 16:15:46 UTC 2023
PRIMARY
Related Record Type Details
TARGET -> ACTIVATOR
Related Record Type Details
ACTIVE MOIETY