Eluxadoline

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P281：Vorgeschriebene persönliche Schutzausrüstung verwenden.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P405：Unter Verschluss aufbewahren.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Eluxadoline Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  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.

• Verwenden

  Eluxadoline is an orally-active drug used to reduce symptoms of irritable bowel syndrome such as diarrhea and abdominal pain.

• 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.

• Pharmakokinetik

  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

• Synthese

  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.

  

• Arzneimittelwechselwirkung

  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.

• Stoffwechsel

  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.

Eluxadoline Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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