Naloxegol

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Naloxegol
Naloxegol.svg
Systematic (IUPAC) name
(5α,6α)-4,5-epoxy-6-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-17-(2-propen-1-yl)morphinan-3,14-diol
Clinical data
Trade names Movantik, Moventig
AHFS/Drugs.com entry
Licence data US FDA:link
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Protein binding ~4.2%
Metabolism Hepatic (CYP3A)
Biological half-life 6–11 h
Excretion Feces (68%), urine (16%)
Identifiers
CAS Number 854601-70-0
ATC code A06AH03 (WHO)
PubChem CID: 56959087
ChemSpider 28651656
ChEBI CHEBI:82975
Synonyms NKTR-118
Chemical data
Formula C34H53NO11
Molecular mass 651.785 g/mol
  • COCCOCCOCCOCCOCCOCCOCCO[C@H]1CC[C@]2([C@H]3Cc4ccc(c5c4[C@]2([C@H]1O5)CCN3CC=C)O)O
  • InChI=1S/C34H53NO11/c1-3-9-35-10-8-33-30-26-4-5-27(36)31(30)46-32(33)28(6-7-34(33,37)29(35)25-26)45-24-23-44-22-21-43-20-19-42-18-17-41-16-15-40-14-13-39-12-11-38-2/h3-5,28-29,32,36-37H,1,6-25H2,2H3/t28-,29+,32-,33-,34+/m0/s1
  • Key:XNKCCCKFOQNXKV-ZRSCBOBOSA-N

Naloxegol (INN; PEGylated naloxol;[1] trade names Movantik and Moventig) is a peripherally-selective opioid antagonist developed by AstraZeneca, licensed from Nektar Therapeutics, for the treatment of opioid-induced constipation.[2] It was approved in 2014 in adult patients with chronic, non-cancer pain.[3] Doses of 25 mg were found safe and well tolerated for 52 weeks.[4] When given concomitantly with opioid analgesics, naloxegol reduced constipation-related side effects, while maintaining comparable levels of analgesia.[5]

Chemically, naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Specifically, the 5-α-hydroxyl group of α-naloxol is connected via an ether linkage to the free hydroxyl group of a monomethoxy-terminated n=7 oligomer of PEG, shown extending at the lower left of the molecule image at right. The "n=7" defines the number of two-carbon ethylenes, and so the chain length, of the attached PEG chain, and the "monomethoxy" indicates that the terminal hydroxyl group of the PEG is "capped" with a methyl group.[6] The pegylation of the 5-α-hydroxyl side chain of naloxol prevents the drug from crossing the blood-brain barrier (BBB).[5] As such, it can be considered the antithesis of the peripherally-acting opiate loperamide which is utilized as an opiate-targeting anti-diarrheal agent that does not cause traditional opiate side-effects due to its inability to accumulate in the central nervous system in normal subjects.

Naloxegol was previously a Schedule II drug in the United States because of its chemical similarity to opium alkaloids, but was recently reclassified as a prescription drug after the FDA concluded that the impermeability of the blood-brain barrier to this compound made it non-habit-forming, and so without the potential for abuse -- specifically, naloxegol was officially decontrolled on 23. January 2015. [7]

As an opiate antagonist, it is not expected to be capable of inducing the euphoria and anxiolytic effects which are generally cited as the desirable effects of commonly abused opiates (all of which are opiate agonists) if it were to cross the BBB; it would in fact reverse the effects of opiate drugs of abuse if it entered the central nervous system.

See also

References and notes

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  6. Technically, the molecule that is attached via the ether link is O-methyl-heptaethylene glycol [that is, methoxyheptaethylene glycol, CH3OCH2CH2O(CH2CH2O)5CH2CH2OH], molecular weight 340.4, CAS number 4437-01-8. See Lua error in package.lua at line 80: module 'strict' not found.
  7. http://www.deadiversion.usdoj.gov/fed_regs/rules/2015/fr0123_3.htm


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