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Naldemedine

PubChem CID
54732242
Structure
Naldemedine_small.png
Naldemedine_3D_Structure.png
Molecular Formula
Synonyms
  • NALDEMEDINE
  • 916072-89-4
  • UNII-03KSI6WLXH
  • 03KSI6WLXH
  • naldemedina
Molecular Weight
570.6 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2011-12-27
  • Modify:
    2025-01-25
Description
Naldemedine is an opioid receptor antagonist. It is a modified form of [DB00704] to which a side chain has been added to increase molecular weight and polar surface area resulting in restricted transport across the blood brain barrier. Naldemedine was approved in 2017 in both the US and Japan for the treatment of Opioid-induced Constipation.
Naldemedine is an Opioid Antagonist. The mechanism of action of naldemedine is as an Opioid Antagonist.
Naldemedine is a peripherally acting opioid antagonist which is used to treat constipation caused by chronic opioid use. Naldemedine has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.
See also: Naldemedine Tosylate (active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Naldemedine.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,7,9-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C32H34N4O6/c1-30(2,29-33-27(35-42-29)18-6-4-3-5-7-18)34-28(39)20-15-32(40)22-14-19-10-11-21(37)25-23(19)31(32,26(41-25)24(20)38)12-13-36(22)16-17-8-9-17/h3-7,10-11,17,22,26,37-38,40H,8-9,12-16H2,1-2H3,(H,34,39)/t22-,26+,31+,32-/m1/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

AXQACEQYCPKDMV-RZAWKFBISA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC(C)(C1=NC(=NO1)C2=CC=CC=C2)NC(=O)C3=C([C@H]4[C@@]56CCN([C@@H]([C@@]5(C3)O)CC7=C6C(=C(C=C7)O)O4)CC8CC8)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C32H34N4O6
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 UNII

2.3.3 ChEMBL ID

2.3.4 DrugBank ID

2.3.5 DSSTox Substance ID

2.3.6 KEGG ID

2.3.7 Metabolomics Workbench ID

2.3.8 NCI Thesaurus Code

2.3.9 Nikkaji Number

2.3.10 PharmGKB ID

2.3.11 Pharos Ligand ID

2.3.12 RXCUI

2.3.13 Wikidata

2.3.14 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 17-(cyclopropylmethyl)-6,7-didehydro-4,5alpha-epoxy-3,6,14-trihydroxy-N-(2-(3-phenyl- 1,2,4-oxadiazol-5-yl)propan-2-yl)morphinan-7-carboxamide
  • naldemedine
  • S-297995
  • Symproic

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
570.6 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
3.2
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
9
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
570.24783482 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
570.24783482 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
141 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
42
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1140
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
4
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

Slightly soluble
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
Human drugs -> Drugs for constipation, Peripheral opioid receptor antagonists -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

For the treatment of opioid-induced constipation.
Rizmoic is indicated for the treatment of opioid-induced constipation (OIC) in adult patients who have previously been treated with a laxative.

6.2 LiverTox Summary

Naldemedine is a peripherally acting opioid antagonist which is used to treat constipation caused by chronic opioid use. Naldemedine has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.

6.3 Drug Classes

Gastrointestinal Agents; Opioid Antagonists

6.4 FDA National Drug Code Directory

6.5 Drug Labels

Drug and label

6.6 Clinical Trials

6.6.1 ClinicalTrials.gov

6.6.2 EU Clinical Trials Register

6.6.3 NIPH Clinical Trials Search of Japan

6.7 EMA Drug Information

1 of 2
Medicine
Category
Human drugs
Therapeutic area
Constipation
Active Substance
Naldemedine tosilate
INN/Common name
naldemedine
Pharmacotherapeutic Classes
Drugs for constipation, Peripheral opioid receptor antagonists
Status
This medicine is authorized for use in the European Union
Company
Shionogi B.V.
Market Date
2019-02-18
2 of 2
Type
Paediatric investigation
Active Substance
Therapeutic Area
Gastroentology-Hepatology
Drug Form
Tablet, Powder for oral suspension
Administration Route
Oral use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2021-09-08

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

Naldemedine is an opioid receptor antagonist with restricted movement across the blood brain barrier. This allows it to antagonize the periperal effects of opioid drugs such as constipation without interfering with the effects on the central nervous system.

7.2 FDA Pharmacological Classification

1 of 2
FDA UNII
03KSI6WLXH
Active Moiety
NALDEMEDINE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Opioid Antagonist
Pharmacological Classes
Mechanisms of Action [MoA] - Opioid Antagonists
FDA Pharmacology Summary
Naldemedine is an Opioid Antagonist. The mechanism of action of naldemedine is as an Opioid Antagonist.
2 of 2
Non-Proprietary Name
NALDEMEDINE
Pharmacological Classes
Opioid Antagonist [EPC]; Opioid Antagonists [MoA]

7.3 ATC Code

A06AH05

A - Alimentary tract and metabolism

A06 - Drugs for constipation

A06A - Drugs for constipation

A06AH - Peripheral opioid receptor antagonists

A06AH05 - Naldemedine

7.4 Absorption, Distribution and Excretion

Absorption
Tmax is 0.75 h. Administration with a high-fat meal reduces Cmax by 35% and increases Tmax to 2.5 h.
Route of Elimination
57% of naldemedine is excreted in the urine with 16-18% as the parent compound and 35% is excreted in the feces.
Volume of Distribution
The apparent volume of disribution during the terminal phase is 155 L

7.5 Metabolism / Metabolites

Naldemedine is mainly metabolized to nor-naldemedine by CYP3A. Some metabolism to naldemedine-3-glucuronide occurs via UGT1A3. Both metabolites are acitive but less potent than naldemedine. The relative exposures of these metabolites are 9-13% and <3% for nor-naldemedine and naldemedine-3-glucuronide respectively. Naldemedine is also cleaved in the intestine to form benzamidine and naldemedine carboxylic acid.

7.6 Biological Half-Life

The terminal elimination half life is 11 h.

7.7 Mechanism of Action

Naldemedine binds to and antagonizes mu-, delta-, and kappa-opioid receptors. The binding of opioid agonists to peripheral mu-opioid receptors slows the transit of feces through the intestine resulting in constipation. By antagonizing mu-opioid receptors, naldemedine inhibits this effect.

8 Use and Manufacturing

8.1 Uses

8.1.1 Use Classification

Human drugs -> Drugs for constipation, Peripheral opioid receptor antagonists -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans

9 Toxicity

9.1 Toxicological Information

9.1.1 Hepatotoxicity

Therapy with naldemedine has not been linked to serum enzyme elevations or to clinically apparent liver injury. In preregistration studies, liver test abnormalities arose in less than 1% of treated patients but were transient, mild and not associated with symptoms. There were no reported cases of liver injury with jaundice or symptoms. Since its approval and more widescale use, there have been no published reports of hepatotoxicity attributed to naldemedine.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

9.1.2 Protein Binding

Naldemedine is 93-94% bound to human plasma proteins.

10 Associated Disorders and Diseases

11 Literature

11.1 Consolidated References

11.2 NLM Curated PubMed Citations

11.3 Springer Nature References

11.4 Chemical Co-Occurrences in Literature

11.5 Chemical-Gene Co-Occurrences in Literature

11.6 Chemical-Disease Co-Occurrences in Literature

12 Patents

12.1 Depositor-Supplied Patent Identifiers

12.2 WIPO PATENTSCOPE

12.3 Chemical Co-Occurrences in Patents

12.4 Chemical-Disease Co-Occurrences in Patents

12.5 Chemical-Gene Co-Occurrences in Patents

13 Interactions and Pathways

13.1 Chemical-Target Interactions

13.2 Drug-Drug Interactions

13.3 Drug-Food Interactions

  • Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of naldemedine.
  • Take with or without food.

14 Biological Test Results

14.1 BioAssay Results

15 Classification

15.1 MeSH Tree

15.2 NCI Thesaurus Tree

15.3 KEGG: ATC

15.4 KEGG: Target-based Classification of Drugs

15.5 KEGG: Drug Groups

15.6 WHO ATC Classification System

15.7 FDA Pharm Classes

15.8 ChemIDplus

15.9 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

15.10 ChEMBL Target Tree

15.11 NORMAN Suspect List Exchange Classification

15.12 EPA DSSTox Classification

15.13 MolGenie Organic Chemistry Ontology

16 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/
    (5α)-17-(Cyclopropylmethyl)-6,7-didehydro-4,5-epoxy-3,6,14-trihydroxy-N-[1-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]morphinan-7-carboxamide
    https://commonchemistry.cas.org/detail?cas_rn=916072-89-4
  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
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. 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
  6. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  7. 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
  8. 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
  9. 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
  10. DailyMed
  11. 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
  12. LiverTox
  13. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  14. 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
  15. EU Clinical Trials Register
  16. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  17. National Drug Code (NDC) Directory
    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
  18. Japan Chemical Substance Dictionary (Nikkaji)
  19. 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
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  20. Metabolomics Workbench
  21. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  22. NIPH Clinical Trials Search of Japan
  23. 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
  24. 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/
    Naldemedine
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  25. Therapeutic Target Database (TTD)
  26. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  27. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  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. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  34. PATENTSCOPE (WIPO)
CONTENTS