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Omaveloxolone

PubChem CID
71811910
Structure
Omaveloxolone_small.png
Omaveloxolone_3D_Structure.png
Molecular Formula
Synonyms
  • Omaveloxolone
  • 1474034-05-3
  • RTA-408
  • RTA 408
  • Nrf1-activator-1
Molecular Weight
554.7 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2013-11-18
  • Modify:
    2025-01-11
Description
Omaveloxolone is a semi-synthetic triterpenoid drug. It is an Nrf2 activator that is approved for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older. It has a role as an antioxidant, an anti-inflammatory agent, a cardioprotective agent and an antineoplastic agent. It is a pentacyclic triterpenoid, a secondary carboxamide, a nitrile, an organofluorine compound and a cyclic terpene ketone. It derives from a hydride of an oleanane.
Omaveloxolone (RTA-408) is a semisynthetic oleanane triterpenoid with antioxidant and anti-inflammatory properties. Omaveloxolone acts as an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that mitigates oxidative stress. In patients with Friedreich's ataxia, a genetic disease involving mitochondrial dysfunction, the Nrf2 pathway is impaired, and Nrf2 activity is lower. Therefore, the use of Nrf2 activators such as omaveloxolone represents a therapeutic advantage in this group of patients. In February 2023, omaveloxolone was approved by the FDA for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older. The use of omaveloxolone for the treatment of conditions involving mitochondrial dysfunction and oxidative stress has also been evaluated.
The mechanism of action of omaveloxolone is as a Cytochrome P450 3A4 Inducer, and Cytochrome P450 2C8 Inducer.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Omaveloxolone.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydropicen-4a-yl]-2,2-difluoropropanamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C33H44F2N2O3/c1-27(2)11-13-33(37-26(40)32(8,34)35)14-12-31(7)24(20(33)17-27)21(38)15-23-29(5)16-19(18-36)25(39)28(3,4)22(29)9-10-30(23,31)6/h15-16,20,22,24H,9-14,17H2,1-8H3,(H,37,40)/t20-,22-,24-,29-,30+,31+,33-/m0/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RJCWBNBKOKFWNY-IDPLTSGASA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 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)NC(=O)C(C)(F)F
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C33H44F2N2O3
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 KEGG ID

2.3.9 Metabolomics Workbench ID

2.3.10 NCI Thesaurus Code

2.3.11 RXCUI

2.3.12 Wikidata

2.3.13 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • N-(11-cyano-2,2,6a,6b,9,9,12a-heptmethyl-10,14-dioxo-1,3,4,5,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-2H-picen-4a-yl)-2-2-difluoropropionamide
  • Omaveloxolone
  • RTA 408
  • RTA-408

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
554.7 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
6.7
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
554.33199959 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
554.33199959 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
87 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
40
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1320
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
7
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Solubility

Practically insoluble
FDA label

3.2.2 Dissociation Constants

pKa
7.26
FDA label

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human
Human drug -> Prescription
Human drug -> Active ingredient (OMAVELOXOLONE)
Paediatric drug

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

Omaveloxolone is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.
Treatment of Friedreich's ataxia

6.2 Drug Classes

Breast Feeding; Lactation; Milk, Human

6.3 FDA Approved Drugs

6.4 FDA Orange Book

6.5 FDA National Drug Code Directory

6.6 Drug Labels

Drug and label
Active ingredient and drug

6.7 Clinical Trials

6.7.1 ClinicalTrials.gov

6.7.2 EU Clinical Trials Register

6.8 EMA Drug Information

Type
Paediatric investigation
Active Substance
Therapeutic Area
Neurology
Drug Form
Age appropriate oral formulation, Capsule, hard
Administration Route
Gastric use, Oral use
Decision Type
P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s)
Decision Date
2022-06-10

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

The MOXIe study showed that after 4 weeks of administration, the use of omaveloxolone led to robust dose‐dependent changes at 80 ‐300 mg/day.. The effect of omaveloxolone on QTc interval has yet to be defined. The use of omaveloxolone can lead to an elevation in hepatic transaminases (both aspartate transaminase and alanine transaminase) and an increase in B-type natriuretic peptide (BNP), a marker of cardiac function. It can also cause changes in cholesterol.

7.2 FDA Pharmacological Classification

1 of 2
FDA UNII
G69Z98951Q
Active Moiety
OMAVELOXOLONE
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inducers
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 2C8 Inducers
FDA Pharmacology Summary
The mechanism of action of omaveloxolone is as a Cytochrome P450 3A4 Inducer, and Cytochrome P450 2C8 Inducer.
2 of 2
Non-Proprietary Name
OMAVELOXOLONE
Pharmacological Classes
Cytochrome P450 3A4 Inducers [MoA]; Cytochrome P450 2C8 Inducers [MoA]

7.3 Absorption, Distribution and Excretion

Absorption
Between 50 mg (0.33 times the recommended dosage) and 150 mg, the AUC of omaveloxolone increased in a dose-dependent and dose-proportional manner. However, at the same dose range, the Cmax increased in a less than dose-proportional manner in healthy fasted subjects. The median time to achieve peak plasma concentration was 7 to 14 hours. Compared to fasted conditions, the AUC0-inf and Cmax of omaveloxolone were 350% and 15% higher with a high-fat meal (800 to 1000 calories, with 150, 250, and 500 to 600 calories coming from protein, carbohydrate, and fat, respectively).
Route of Elimination
Omaveloxolone is mainly excreted in feces. In healthy subjects given a single oral dose of radiolabeled omaveloxolone (150 mg), about 92% and 0.1% of the dose were recovered in feces and urine, respectively. Approximately 91% of the omaveloxolone found in feces was recovered within 96 hours after administration.
Volume of Distribution
Omaveloxolone has an apparent volume of distribution of 7361 L.
Clearance
Omaveloxolone has an apparent plasma clearance of 109 L/hr.

7.4 Metabolism / Metabolites

Omaveloxolone is mainly metabolized by CYP3A, although CYP2C8 and CYP2J2 play also a minor role.

7.5 Biological Half-Life

Omaveloxolone has a terminal half-life of 57 hours.

7.6 Mechanism of Action

The mechanism of action of omaveloxolone has not been fully elucidated; however, its therapeutic effect in patients with Friedreich's ataxia may be linked to its ability to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Nrf2 is a transcription factor that mitigates oxidative stress. In normal conditions, Nrf2 levels are regulated by Kelch-like ECH-associated protein 1 (KEAP1), which binds to Nrf2, prevents Nrf2 translocation to the nucleus, and degrades it by ubiquitination. In the presence of oxidative stress, the ubiquitination system is disrupted. Nrf2 accumulates and translocates to the nucleus, where it promotes the expression of genes against oxidative stress. In patients with Friedreich's ataxia, the Nrf2 signaling pathway is dysfunctional. In Friedreich's ataxia models, Nrf2 has a lower activity; therefore, Nrf2 activators such as omaveloxolone represent a therapeutic opportunity. A study has shown that omaveloxolone binds to KEAP1, inhibiting its interaction with Nrf2 and promoting the translocation of Nrf2 to the nucleus. Aside from activating Nrf2, omaveloxolone also inhibits the NF-κB signalling pathway, promoting antioxidative, anti-inflammatory, and antiapoptotic mechanisms.

8 Use and Manufacturing

8.1 Uses

8.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 GHS Classification

GHS Hazard Statements

Not Classified

Reported as not meeting GHS hazard criteria by 1 of 1 companies. For more detailed information, please visit ECHA C&L website.

9.1.2 Hazard Classes and Categories

Not Classified

10 Toxicity

10.1 Toxicological Information

10.1.1 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the clinical use of omaveloxolone during breastfeeding. Because it is 97% protein bound, exposure of the breastfed infant is likely to be low. Until more data become available, omaveloxolone should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

10.1.2 Protein Binding

The protein binding of omaveloxolone is 97%.

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Springer Nature References

12.4 Chemical Co-Occurrences in Literature

12.5 Chemical-Gene Co-Occurrences in Literature

12.6 Chemical-Disease Co-Occurrences in Literature

13 Patents

13.1 Depositor-Supplied Patent Identifiers

13.2 WIPO PATENTSCOPE

13.3 FDA Orange Book Patents

13.4 Chemical Co-Occurrences in Patents

13.5 Chemical-Disease Co-Occurrences in Patents

13.6 Chemical-Gene Co-Occurrences in Patents

14 Interactions and Pathways

14.1 Chemical-Target Interactions

14.2 Drug-Drug Interactions

14.3 Drug-Food Interactions

Take on an empty stomach. Take omaveloxolone capsules on an empty stomach at least 1 hour before eating. Compared to fasting conditions, a high-fat meal increased the Cmax and AUC by approximately 350% and 15%, respectively.

15 Biological Test Results

15.1 BioAssay Results

16 Classification

16.1 MeSH Tree

16.2 NCI Thesaurus Tree

16.3 ChEBI Ontology

16.4 KEGG: Target-based Classification of Drugs

16.5 KEGG: Drug Groups

16.6 ChemIDplus

16.7 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

16.8 ChEMBL Target Tree

16.9 UN GHS Classification

16.10 NORMAN Suspect List Exchange Classification

16.11 EPA DSSTox Classification

16.12 FDA Drug Type and Pharmacologic Classification

16.13 PFAS and Fluorinated Organic Compounds in PubChem

16.14 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
    N-(2-Cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2,2-difluoropropanamide
    https://commonchemistry.cas.org/detail?cas_rn=1474034-05-3
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    N-(2-Cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2,2-difluoropropanamide
    https://comptox.epa.gov/dashboard/DTXSID101138251
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    (1E)-N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-4a(2H)-picenyl]-2,2-difluoropropanimidic acid; N-((4aR,6aR,6bS,12aS,14aR,14bR)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen- 4a-yl)-2,2-difluoropropanamide
    https://echa.europa.eu/substance-information/-/substanceinfo/100.392.729
    (1E)-N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydro-4a(2H)-picenyl]-2,2-difluoropropanimidic acid; N-((4aR,6aR,6bS,12aS,14aR,14bR)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen- 4a-yl)-2,2-difluoropropanamide (EC: 962-491-6)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/352564
  6. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. ChEBI
  8. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  9. NCI Thesaurus (NCIt)
    LICENSE
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    https://www.cancer.gov/policies/copyright-reuse
  10. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  11. ChEMBL
    LICENSE
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    http://www.ebi.ac.uk/Information/termsofuse.html
  12. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  13. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  14. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  15. Therapeutic Target Database (TTD)
  16. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  17. DailyMed
  18. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  19. Drugs and Lactation Database (LactMed)
  20. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. EU Clinical Trials Register
  22. FDA Orange Book
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  23. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  24. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  25. Metabolomics Workbench
  26. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  27. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    N-(11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-4a-yl)-2,2-difluoropropanamide
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  28. Springer Nature
  29. Wikidata
  30. Wikipedia
  31. PubChem
  32. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
  33. GHS Classification (UNECE)
  34. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  35. PATENTSCOPE (WIPO)
CONTENTS