Bardoxolone methyl

Base Information

• Chemical Name: Bardoxolone methyl
• CAS No.: 218600-53-4
• Molecular Formula: C32H43 N O4
• Molecular Weight: 505.698
• Hs Code.: 2926909090
• European Community (EC) Number: 606-850-4
• NSC Number: 713200
• UNII: CEG1Q6OGU1
• DSSTox Substance ID: DTXSID5048764
• Nikkaji Number: J1.214.650G
• Wikipedia: Bardoxolone_methyl
• Wikidata: Q4860208
• NCI Thesaurus Code: C98250
• Pharos Ligand ID: YSAB3DBC197N
• Metabolomics Workbench ID: 149606
• ChEMBL ID: CHEMBL1762621
• Mol file: 218600-53-4.mol

Synonyms:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid methyl ester;bardoxolone methyl;CDDO methyl ester;CDDO-Me;methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate;RTA-402

Chemical Property of Bardoxolone methyl

Chemical Property:

• Vapor Pressure: 2.15E-14mmHg at 25°C
• Melting Point: 215-223°C
• Boiling Point: 600.8°Cat760mmHg
• Flash Point: 256.5°C
• PSA: 84.23000
• Density: 1.15g/cm³
• LogP: 6.37898
• Storage Temp.: Refrigerator
• Solubility.: Chloroform (Slightly), Methanol (Slightly)
• XLogP3: 6.7
• Hydrogen Bond Donor Count: 0
• Hydrogen Bond Acceptor Count: 5
• Rotatable Bond Count: 2
• Exact Mass: 505.31920885
• Heavy Atom Count: 37
• Complexity: 1210

Purity/Quality:

99%, ^*data from raw suppliers

CDDO Methyl Ester ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC1(CCC2(CCC3(C(C2C1)C(=O)C=C4C3(CCC5C4(C=C(C(=O)C5(C)C)C#N)C)C)C)C(=O)OC)C
• Isomeric SMILES: C[C@@]12CC[C@]3(CCC(C[C@H]3[C@H]1C(=O)C=C4[C@]2(CC[C@@H]5[C@@]4(C=C(C(=O)C5(C)C)C#N)C)C)(C)C)C(=O)OC
• Recent ClinicalTrials: Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension - CATALYST
• Recent EU Clinical Trials: An Extended Access Program to Assess Long Term Safety of Bardoxolone Methyl in Patients with Chronic Kidney Disease
• Recent NIPH Clinical Trials: An Extended Access Program to Assess Long Term Safety of Bardoxolone Methyl in Patients with Chronic Kidney Disease
• Description: Bardoxolone methyl is an antioxidant inflammatory modulator that reversibly interacts with critical free thiol groups of cysteine residues on KEAP-1 and other target proteins, inducing the trans-location of Nrf-2 to the nucleus and the activation of several genes, including glutathione S-transferase, haeme oxygenase, and other components of the cytoprotective response (Thomas et al., 2012). At high doses, bardoxolone methyl may also interact with other proteins, including PPAR-gamma, tubulin, and the kinase activa-tor IKK.
• Uses: Bardoxolone methyl is an antiinflam-matory drug that activates the Nrf2-Keap1 pathway,resulting in inhibition of the proinflammatory cytokine Nf-κB.Bardoxolone methyl (BARD, CDDO-ME, RTA-402) is an orally bioavailable semi-synthetic triterpenoid compound based of the scaffold of oleanolic acid. It was developed by Reata Pharmaceuticals as an activator of the Nrf2 antioxidant pathway. It has been tested in clinical trials for kidney disease, pulmonary hypertension, and cancer. CDDO Methyl Ester is a synthetic triterpenoid that inhibits IκBα kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor κB-regulated gene products in human leukemic cells. CDDO Methyl Ester is a novel therapeutic agent in the treatment of acute myeloid leukemia and in the treatment of pancreatic cancer as well as other forms of cancer.
• Clinical Use: Bardoxolone methyl is a synthetic compound derived from oleanolic acid,whichactivates the Keap1-Nrf2 pathway and regulates inflammation in the kidney. In the Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM)study，patients with CKD and diabetes wererandomly assigned to receive either bardoxolone methyl or placebo for 52 weeks.Bardoxolone methyl significantly increased the mean eGFR compared with placebo at 24 weeks. The improvement lasted for another 28 weeks. Adverse events, particularly muscle spasms，were more frequent in the bardoxolone methyl group.The Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events study was designed to confirm the findings of the BEAM study. Unfortunately the study was prematurely stopped owing to unacceptable high rates of cardiovascular events in patients treated with bardoxolone methyl at a medianduration of 7 months，and no benefit wasobserved about the risk of ESRD. The beneficial effects of an Nrf2 agonist called dh404, which is a derivative of bardoxolone methyl, via reduction in inflammation and oxidative stress but only at low doses have recently been shown in mice. This finding rekindles the interests on renoprotection via activation of the Nrf2 pathway in DKD.

Technology Process of Bardoxolone methyl

There total 19 articles about Bardoxolone methyl which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 96.0%

methanol (67-56-1) + bardoxolone (218600-44-3) → bardoxolone methyl (218600-53-4)

Guidance literature:

bardoxolone; With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20 ℃; for 1.16667h; Cooling with ice;

methanol; In dichloromethane; for 1h;

Reference yield: 92.0%

1,2-dihydro-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (305818-40-0) → bardoxolone methyl (218600-53-4)

Guidance literature:

With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In benzene; for 0.5h; Heating;

DOI:10.1021/jm0002230

Reference yield: 89.0%

C31H43IO4 (1198076-59-3) + copper(l) cyanide → bardoxolone methyl (218600-53-4)

Guidance literature:

With potassium iodide; In N,N-dimethyl-formamide; at 120 ℃; for 16h; Inert atmosphere;

DOI:10.1021/ol400399x

upstream raw materials:

1,2-dihydro-2-cyano-3,12-dioxooleana-1,9⁽¹¹⁾-dien-28-oic acid methyl ester

methyl 3β-hydroxy-12-oxoolean-9(11)-en-28-oate

methyl 3β-acetoxy-12-oxoolean-9(11)-en-28-oate

methyl 3,12-dioxoolean-9⁽¹¹⁾-en-28-oate

Downstream raw materials:

bardoxolone

Refernces

• 1、 -. "Oleanolic acid derivative with conjugated diene structure C ring and preparation method and application thereof". Paragraph 0092-0095; 0109-0112. . Retrieved 2020/07/21.
• 2、 -. "Improvement of synthesis method of 2-cyano-3,12-dioxo oleanane-1,9 (11)-diene-28-carboxylic acid". . . Retrieved 2017/08/28.