Monday, August 1, 2016

Naloxegol | µ-Opioid Receptor Antagonist | Treatment of Opioid-induced Constipation

Naloxegol is an oral polyethylene glycol (PEG) derivative of naloxone, a peripherally acting µ-opioid receptor antagonist (PAMORA) with limited potential for interfering with centrally mediated opioid analgesia. The incorporation of a polyethylene glycol moiety aims at inhibiting naloxone’s capacity to cross the blood-brain barrier, while preserving the affinity for the µ-opioid receptor [1].
Opioid-induced bowel dysfunction (OIBD) represents a broad spectrum of symptoms that result from the actions of opioids on the CNS as well as the gastrointestinal tract. The majority of gastrointestinal effects seem to be mediated by the high number of µ-receptors that are expressed in the enteric nervous system. Naloxegol was more effective than placebo in increasing the number of spontaneous bowel movements in patients with opioid-induced constipation, including those with an inadequate response to laxatives.
Recognition of Naloxegol as a useful option in the treatment of opioid-induced constipation resulted in its approval by US-FDA for adult patients with chronic, non-cancer pain in 2014.

Naloxegol: 2D and 3D Structure

Naloxegol Synthesis

US20050136031A1: The patent reports detailed synthetic procedures to manufacture gram quantities of Naloxegol. The synthesis starts with Naloxone which was treated with methoxyethyl chloride in the presence of Hunig’s base to give the protected ketone. Reduction of the ketone with potassium tri-sec-butylborohydride exclusively provided the α-alcohol in 85% yield. Deprotonation of the alcohol with sodium hydride followed by alkylation with CH3(OCH2CH2)7Br  provided the pegylated Naloxone in 88% yield.


1H NMR (Estimated) for Naloxegol

Sideeffects: Most adverse events (AEs) in clinical trials were mild to moderate in severity, occurred early in treatment and resolved upon continued treatment.
Abdominal pain was the only adverse event that occurred in greater than10 % of Naloxegol (12.5 mg or 25 mg/day) recipients in the pivotal clinical trials, named KODIAC-04 and KODIAC-05, respectively. Other reported AEs are diarrhoea (2.8 %), abdominal pain (1.9 %) and upper abdominal pain (1.4 %) in KODIAC-04 and abdominal pain (3.9 %), diarrhoea (3.4 %), nausea (1.7 %) and vomiting (1.7 %) in KODIAC-05.

1. Garnock-Jones, K. P.; et. al. Naloxegol: A Review of Its Use in Patients with Opioid-Induced Constipation. Drugs 2015, 75(4), 419-25. (FMO only)
2. Bentley, M.; et. al. Chemically modified small molecules. US20050136031A1