Definition
ChEBI: An amino acid amide obtained by the formal condensation of the carboxy group of 4-carbamoyl-2,6-dimethyl-L-phenylalanine with the secondary amino group of 2-methoxy-5-({[(1S)-1-(4-phenylimidazol-2-yl)ethyl]amino}methyl)ben
oic acid. It has mixed opioid receptor activity and is used for treatment of irritable bowel syndrome with diarrhoea.
Description
Eluxadoline, originally developed
by Janssen and currently marketed by Allergan (formerly
Actavis), was approved in May 2015 by the FDA for the
treatment of diarrhea-predominant irritable bowel syndrome
(IBS-D). Eluxadoline, an orally dosed agent, employs a
unique mechanism for IBS-D treatment, as it functions
simultaneously as a μ- and κ-opioid receptor agonist and a δ-
opioid receptor antagonist, leading to a first-in-class therapy
for treatment of IBS-D. Specifically, in animal studies,
eluxadoline was found to interact with opioid receptors in the
gut, inhibiting neurogenically mediated secretion and reducing
intestinal contractility. Additionally, the treatment led to a
decrease in stress-induced acceleration of upper GI transit
without causing rebound constipation, earning its mark as
a first-line therapeutic treatment for IBS-D. In two phase III
clinical trials of over 2400 patients with IBS-D, patients taking
eluxadoline showed a greater improvement toward the end
point (≥30% improvement from their baseline IBS-D score on
at least 50% of days treated with eluxadoline) compared to
patients treated with placebo.
Uses
Eluxadoline is an orally-active drug used to reduce symptoms of irritable bowel syndrome such as diarrhea and abdominal pain.
Pharmacokinetics
Following oral administration of 100 mg VIBERZI in healthy subjects, the Cmax of eluxadoline was approximately 2 to 4 ng/mL, and AUC was 12 to 22 ng. h/mL. Eluxadoline has approximately linear pharmacokinetics with no accumulation upon repeated twice-daily dosing. The variability of eluxadoline pharmacokinetic parameters ranges from 51% to 98%.
Absorption: The absolute bioavailability of eluxadoline has not been determined. The median Tmax value was 1.5 hours (1 to 8 hours) under fed conditions and 2 hours (range: 0.5 to 6 hours) under fasting conditions.
The administration of VIBERZI with a high-fat meal that contained approximately 800 to 1000 total calories, with 50% of calories derived from fat content, decreased the Cmax of eluxadoline by 50% and AUC by 60%.
Distribution: Plasma protein binding of eluxadoline was 81%.
Elimination: The mean plasma elimination half-life of eluxadoline ranged from 3.7 hours to 6 hours.
Metabolism: The metabolism of eluxadoline is not established. There is evidence that glucuronidation can occur to form an acyl glucuronide metabolite.
Excretion: Following a single oral dose of 300 mg [14C] eluxadoline in healthy male subjects, 82.2% of the total radioactivity was recovered in feces within 336 hours and less than 1% was recovered in urine within 192 hours.
Clinical Use
Mixed mu-opioid receptor agonist, kappa-opioid receptor
agonist, and a-delta opioid receptor antagonist:
Treatment of irritable bowel syndrome with
diarrhoea
Synthesis
The synthesis of eluxadoline begins with preparation of
advanced coupling component 85, which could be completed
via a four-step route from commercially available N-Bocprotected
aminoester 83 . Triflate formation using N-phenyltrifluoromethanesulfinimide in DCM under
basic conditions led to nearly quantitative yield of the desired
triflate, which was subjected to a carbonylation reaction to yield
aryl acid 84 in 94% yield. Employing NH4Cl as a source of
ammonia, amidation of 84 took place in the presence of
PyBOP/HOBt and DIPEA in DMF. Finally, acid 85 was
revealed upon methyl ester saponification with aqueous LiOH
in THF. This sequence provided 85 without purification.
With coupling component 85 in hand and initiated from a HOBt and EDC?¤HCl-mediated coupling of commercial
N-Cbz-L-alanine (86) with commercial 2-amino acetophenone
hydrochloride (87) to provide intermediate 88 in 83%
yield. Addition of NH4OAc and AcOH to a suspension
of 88 in refluxing xylenes furnished the desired imidazole in
excellent yield (95%). Submission of this N-Cbz-imidazole to
hydrogenation conditions (H2, Pd/C, MeOH) enabled
liberation of the free amine to access 89 in quantitative yield
following filtration and concentration. From intermediate 89,
reductive amination with commercially available aryl aldehyde
90 under standard conditions (NaBH4, MeOH) followed by
subsequent coupling of the corresponding crude amine with acid 85 using HOBt/EDC?¤HCl enabled formation of the
carbon framework of eluxadoline (91). Saponification of the
ester within 91 with LiOH in MeOH/THF yielded the
corresponding acid in quantitative yield. Immediate subjection
of this intermediate to acidic conditions (HCl in EtOAc/THF)
led to N-Boc cleavage and isolation of eluxadoline (XII) as the
bis-HCl salt in 71% yield, requiring no further purification.
It should be noted that since this initial report, additional
details for the isolation of eluxadoline in high purity in various
crystal forms and as a zwitterion have been reported,66 although
most reported routes described isolation of this drug in its HCl
salt form.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by
rifampicin - avoid.
Antivirals: concentration possibly increased by
atazanavir, lopinavir, ritonavir, saquinavir and
tipranavir - avoid.
Ciclosporin: concentration of eluxadoline increased
- avoid.
Lipid-lowering agents: concentration possibly
increased by gemfibrozil - avoid.
Metabolism
Eluxadoline is mainly excreted in the faeces, either as
unabsorbed active substance or via the biliary system with
the kidney playing a minimal role in elimination.
