Identification

Name
Naldemedine
Accession Number
DB11691
Type
Small Molecule
Groups
Approved, Investigational
Description

Naldemedine is an opioid receptor antagonist [Label]. It is a modified form of Naltrexone 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.

Structure
Thumb
Synonyms
Not Available
External IDs
S-297995
Product Ingredients
IngredientUNIICASInChI Key
Naldemedine tosylateV1N8F1RVVO1345728-04-2WCYDLROFMZJJLE-RTMHEQJQSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SymproicTablet.2 mg/1OralPurdue Pharma LP2017-03-23Not applicableUs
SymproicTablet0.2 mg/1OralShionogi2017-03-23Not applicableUs
Categories
UNII
03KSI6WLXH
CAS number
916072-89-4
Weight
Average: 570.646
Monoisotopic: 570.247834831
Chemical Formula
C32H34N4O6
InChI Key
AXQACEQYCPKDMV-RZAWKFBISA-N
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
IUPAC Name
(1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,14,17-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7,9,11(18),14-tetraene-15-carboxamide
SMILES
[H][C@@]12OC3=C4C(C[C@@]5([H])N(CC6CC6)CC[C@@]14[C@@]5(O)CC(C(=O)NC(C)(C)C1=NC(=NO1)C1=CC=CC=C1)=C2O)=CC=C3O

Pharmacology

Indication

For the treatment of opioid-induced constipation [Label].

Associated Conditions
Pharmacodynamics

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

Mechanism of action

Naldemedine binds to and antagonizes mu-, delta-, and kappa-opioid receptors [Label]. 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.

TargetActionsOrganism
AMu-type opioid receptor
antagonist
Human
ADelta-type opioid receptor
antagonist
Human
AKappa-type opioid receptor
antagonist
Human
Absorption

Tmax is 0.75 h [Label]. Administration with a high-fat meal reduces Cmax by 35% and increases Tmax to 2.5 h.

Volume of distribution

The apparent volume of disribution during the terminal phase is 155 L [Label]

Protein binding

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

Metabolism

Naldemedine is mainly metabolized to nor-naldemedine by CYP3A [Label]. 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.

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 [Label].

Half life

The terminal elimination half life is 11 h [Label].

Clearance
Not Available
Toxicity

The most common adverse effects of naldemedine are abdominal pain (11%), diarrhea (7%), nausea (6%), vomiting (3%), and gastroenteritis (3%) [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Naldemedine which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Naldemedine which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Naldemedine which could result in a higher serum level.
Food Interactions
Not Available

References

General References
Not Available
External Links
PubChem Compound
54732242
PubChem Substance
347828056
ChemSpider
28530803
ChEMBL
CHEMBL2105755
Wikipedia
Naldemedine
FDA label
Download (209 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentOpioid Induced Constipation (OIC)3
Not AvailableNot Yet RecruitingNot AvailableOpioid Induced Constipation (OIC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral.2 mg/1
TabletOral0.2 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9108975No2011-11-112031-11-11Us
USRE46365No2008-01-112028-01-11Us
USRE46375No2006-10-052026-10-05Us

Properties

State
Not Available
Experimental Properties
PropertyValueSource
water solubilitySlightly solubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.227 mg/mLALOGPS
logP3.14ALOGPS
logP2.43ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)9.86ChemAxon
pKa (Strongest Basic)9.05ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area141.18 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity165.78 m3·mol-1ChemAxon
Polarizability61.34 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Morphinans
Sub Class
Not Available
Direct Parent
Morphinans
Alternative Parents
Phenanthrenes and derivatives / Phenyloxadiazoles / Tetralins / Coumarans / 1-hydroxy-2-unsubstituted benzenoids / Alkyl aryl ethers / Aralkylamines / Piperidines / Benzene and substituted derivatives / Vinylogous acids
show 13 more
Substituents
Morphinan / Phenanthrene / Phenyl-1,2,4-oxadiazole / Tetralin / Coumaran / Alkyl aryl ether / 1-hydroxy-2-unsubstituted benzenoid / Phenol / Aralkylamine / Monocyclic benzene moiety
show 31 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da

Enzymes

Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da

Drug created on October 20, 2016 14:40 / Updated on November 02, 2018 09:12