218600-53-4 Usage
Description
Bardoxolone methyl, also known as BARD, CDDO-ME, or RTA-402, is an orally bioavailable semi-synthetic triterpenoid compound derived from the scaffold of oleanolic acid. It functions as an antioxidant inflammatory modulator that interacts with critical free thiol groups of cysteine residues on KEAP-1 and other target proteins. This interaction induces the translocation of Nrf-2 to the nucleus, activating several genes involved in the cytoprotective response. Bardoxolone methyl is characterized by its white to off-white solid appearance and has been developed by Reata Pharmaceuticals as an activator of the Nrf2 antioxidant pathway.
Uses
1. Used in Pharmaceutical Industry:
Bardoxolone methyl is used as an anti-inflammatory drug for activating the Nrf2-Keap1 pathway, which results in the inhibition of the pro-inflammatory cytokine Nf-κB. This property makes it a potential candidate for treating various inflammatory conditions.
2. Used in Kidney Disease Treatment:
Bardoxolone methyl is used as a therapeutic agent for kidney disease, as it has demonstrated potential benefits in clinical trials for this application.
3. Used in Pulmonary Hypertension Treatment:
It is also used as a therapeutic agent for pulmonary hypertension, where its anti-inflammatory and antioxidant properties can be beneficial.
4. Used in Cancer Treatment:
Bardoxolone methyl is used as a novel therapeutic agent in the treatment of various forms of cancer, including acute myeloid leukemia and pancreatic cancer. It enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor κB-regulated gene products in human leukemic cells.
5. Used in Drug Development:
Bardoxolone methyl is used in the development of new drugs targeting the Nrf2 antioxidant pathway, which can potentially provide cytoprotective effects and treat a range of diseases with oxidative stress involvement.
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.
Enzyme inhibitor
This oleanane triterpenoid (FW = 505.70 g/mol; CAS 218600-53-4; Solubility: 1 mg/mL DMSO; <1 mg/mL H2O), also known as RTA 402, TP- 155, NSC 713200, CDDO Methyl Ester, and 2-cyano-3,12-dioxooleana- 1,9(11)-dien-28-oic acid methyl ester, targets Inhibitor of nuclear factor Kappa-B Kinase subunit b, or IKKb, a key component of the cytokine activated intracellular signaling pathway that triggers immune responses. Significantly, CDDO methyl ester inhibits proliferation of myeloid leukemia cells, inducing both differentiation and apoptosis. CDDO-Me induces loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding, and DNA fragmentation – all suggesting induction of apoptosis. CDDO-Me induces pro-apoptotic Bax protein that preceded caspase activation. CDDO-Me also inhibits ERK1/2 activation, as indicated by inhibition of mitochondrial ERK1/2 phosphorylation and blocking of Bcl-2 phosphorylation, rendering the latter less anti-apoptotic. CDDO-Me inhibits NF-kB through inhibition of IkBa kinase, resulting in the suppression of expression of NF-kB-regulated gene products (Readouts: IAP2, cFLIP, TRAF1, survivin, and Bcl-2) as well as inhibition of proliferation (Readouts: cyclin d1 and c-myc), and angiogenesis (Readouts: VEGF, Cox-2, and MMP-9). CDDO-Me thus enhances apoptosis induced by TNF and chemotherapeutic agents. Bardoxolone methyl exhibits potent pro-apoptotic and anti-inflammatory activity, potently inhibiting interferon γ-induced nitric oxide synthesis in mouse macrophages, IC50 = 0.1 nM. Bardoxolone methyl pretreatment uniquely confers protection against lipopolysaccharide (LPS) challenge by modulating the in vivo immune response to LPS, indicating that it represents a novel oral agent for use in LPS-mediated inflammatory diseases. Significantly, a number of well-recognized naturally occurring or synthetic anti-inflammatory compounds possessing a Michael-type acceptor (e.g., thymoquinone (TQ), the paracetamol metabolite NAPQI, the 5-LO inhibitor AA-861, and bardoxolone methyl) are all direct covalent 5-LO enzyme inhibitors that target the catalytically relevant Cysteines 416 and 418. Their actiom as irreversible Michael acceptor moietied that interact with required cysteines of proteins/enzymes may expain why they are effective and sustained enzyme activity modulators.
Check Digit Verification of cas no
The CAS Registry Mumber 218600-53-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,1,8,6,0 and 0 respectively; the second part has 2 digits, 5 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 218600-53:
(8*2)+(7*1)+(6*8)+(5*6)+(4*0)+(3*0)+(2*5)+(1*3)=114
114 % 10 = 4
So 218600-53-4 is a valid CAS Registry Number.
InChI:InChI=1/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
218600-53-4Relevant articles and documents
Novel Derivative of Bardoxolone Methyl Improves Safety for the Treatment of Diabetic Nephropathy
Huang, Zhangjian,Mou, Yi,Xu, Xiaojun,Zhao, Di,Lai, Yisheng,Xu, Yuwen,Chen, Cen,Li, Ping,Peng, Sixun,Tian, Jide,Zhang, Yihua
, p. 8847 - 8857 (2017)
Currently, no effective and safe medicines are available to treat diabetic nephropathy (DN). Bardoxolone methyl (CDDO-Me) has displayed promising anti-DN activity as well as serious side effects in clinical trials, probably because the highly reactive α-cyano-α,β-unsaturated ketone (CUK) in ring A of CDDO-Me can covalently bind to thiol functionalities in many biomacromolecules. In this study, we designed and synthesized a γ-glutamyl transpeptidase (GGT)-based and CUK-modified derivative of CDDO-Me (2) to address this issue. 2 can be specifically cleaved by GGT, which is highly expressed in the kidney, to liberate CDDO-Me in situ. It should be noted that 2 exhibited anti-DN efficacy comparable to that of CDDO-Me with much less toxicity in cells and db/db mice, suggesting that its safety is better than CDDO-Me. Our findings not only reveal the therapeutic potential of 2 but also provide a strategy to optimize other synthetic molecules or natural products bearing a pharmacophore like CUK to achieve safer pharmaceutical drugs.
Oleanolic acid derivative with conjugated diene structure C ring and preparation method and application thereof
-
Paragraph 0092-0095; 0109-0112, (2020/07/21)
The invention belongs to the field of medicinal chemistry, and particularly relates to an oleanolic acid derivative with a conjugated diene structure C ring and a preparation method and application thereof. In particular, the invention also provides a pharmaceutical composition comprising an effective amount of the derivative or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; moreover, the derivative or the pharmaceutically acceptable salt thereof can be used for treating inflammation-related diseases and has antitumor activity, and the safety of the compound is improved or equivalent.
Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites
Wong, Michael H. L.,Bryan, Holly K.,Copple, Ian M.,Jenkins, Rosalind E.,Chiu, Pak Him,Bibby, Jaclyn,Berry, Neil G.,Kitteringham, Neil R.,Goldring, Christopher E.,O'Neill, Paul M.,Park, B. Kevin
, p. 2396 - 2409 (2016/04/10)
Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro. We show that one of these analogues, CDDO-epoxide (13), is comparable to 4 in terms of cytotoxicity and potency toward Nrf2 in rat hepatoma cells and stably modifies specific cysteine residues (namely, Cys-257, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in living cells. Supported by molecular modeling, these data demonstrate the value of 13 for identifying site(s) of interaction with pharmacologically relevant targets and informing the continuing development of triterpenoids as novel drug candidates.