Metopimazine

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Metopimazine
Clinical data
Trade namesVogalen, Vogalene
Other namesEXP-999; RP-9965; NG-101
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4-carboxamide
JSmol)
  • O=S(=O)(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCC(C(=O)N)CC4)C
  • InChI=1S/C22H27N3O3S2/c1-30(27,28)17-7-8-21-19(15-17)25(18-5-2-3-6-20(18)29-21)12-4-11-24-13-9-16(10-14-24)22(23)26/h2-3,5-8,15-16H,4,9-14H2,1H3,(H2,23,26) checkY
  • Key:BQDBKDMTIJBJLA-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Metopimazine (

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name), sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting.[1][2][3][4][5][6] It is marketed in Europe, Canada, and South America.[2][5] As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.[6][5]

Metopimazine has

cardiovascular profile.[5] In contrast to metoclopramide, metopimazine does not interact with serotonin 5-HT3 and 5-HT4 receptors.[5]

Medical uses

Metopimazine is an approved

etiologies. The IV formulation is almost exclusively used to treat chemotherapy-induced nausea and vomiting in adults and children.[12]

Adverse effects

Generally, studies in chemotherapy-induced nausea and vomiting suggest that doses of metopimazine higher than approved for common nausea and vomiting conditions tend to be more

adverse events.[13][14][15][16][17][18][19][20][21]
In a
dose-ranging, open-label study in patients undergoing chemotherapy, metopimazine administered orally at 20, 30, 40, 50, or 60 mg every 4 hours (q4h) for 48 hours was used to determine its safety and tolerability. Metopimazine was determined to be safe at a dose of 30 mg administered 6 times daily (180 mg/day). The dose-limiting toxicity to metopimazine was moderate-to-severe dizziness caused by orthostatic hypotension, which was observed beginning at 40 mg every 4 hours for 48 hours. Other side effects were few and mild in severity. A single possibly drug-related extrapyramidal adverse event was observed in a patient in the 60 mg q4h or 360 mg daily dose group.[22]
In a randomized, double-blind comparison of
platinum-based chemotherapy, metopimazine was administered by IV (24-hour continuous infusion) at 35 mg/m2 followed by 30 mg per orally (PO) 4 times a day (120 mg/day) for 4 days. Metopimazine plus ondansetron was more efficacious than ondansetron alone, and adverse reactions were mild and without significant differences between the two treatment groups. However, there was an asymptomatic decrease in standing blood pressure when patients received the combination antiemetic therapy.[19]
In a randomized, double-blind study assessing the efficacy and safety of
gastrointestinal disorders was significantly lower in the metopimazine group, particularly abdominal pain and constipation.[23]

Mechanism of action

Metopimazine, a phenothiazine derivative, is a potent D2/D3 dopamine receptor antagonist. Metopimazine has also shown adrenergic alpha1, histamine H1, serotonin 5HT2a antagonism.[10]

Pharmacokinetics

The pharmacokinetics (PK) profile of metopimazine has been reported as comparable between adults and children. The maximum plasma concentration (Cmax) of metopimazine is reached approximately 60 minutes after oral administration, and the elimination half-life is approximately two hours.

metabolized to metopimazine acid (Tmax ~2 hours), its major metabolite in humans. Metopimazine is primarily metabolized by a liver amidase in humans and therefore present a low risk on drug-drug interaction.[25] Exposure is reduced by ~30% and 50% (area under the curve (AUC) and Cmax, respectively) when metopimazine is administered with food.[26][10]

The bioavailability of metopimazine in humans is low. A 10 mg dose of metopimazine was reported to have an absolute bioavailability under 20%.[26]

Research

Metopimazine mesylate (NG101), a novel formulation of metopimazine, is under clinical development for idiopathic gastroparesis in the United States.[27] Gastroparesis is a debilitating chronic gastrointestinal disorder characterized by delayed gastric emptying without evidence of mechanical obstruction. Symptoms include nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain.[28][29][30]

Synthesis

Thieme Patent:[31] Revised:[32]

For the first step, 2-Methylthiophenothiazine [7643-08-5] (1) is protected by sequential reaction with sodium amide and acetic anhydride to give 1-[2-(Methylthio)-10H-phenothiazin-10-yl]ethanone [23503-69-7] (2). Oxidation with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone. Upon hydrolysis of the acetate this affords 2-(methylsulfonyl)-10h-phenothiazine [23503-68-6] (3). Alkylation with 1-Bromo-3-chloropropane (4) gives 10-(3-chloropropyl)-2-methylsulfonylphenothiazine [40051-30-7] (5). Alkylation with piperidine-4-carboxamide (Isonipecotamide) [39546-32-2] (6) affords metopimazine (7).

References

  1. OCLC 1058412474
    .
  2. ^
    ISBN 978-3-88763-075-1
    .
  3. OCLC 1243535030
    .
  4. PMID 9777292
    .
  5. ^
    PMID 33471485
    .
  6. ^ a b "Metopimazine - Neurogastrx - AdisInsight".
  7. S2CID 220909387
    .
  8. ^ "Vogalene®". www.rxreasoner.com.
  9. ^ "Accueil - ANSM". ansm.sante.fr (in French). Retrieved 26 March 2023.
  10. ^
    S2CID 76202219
    .
  11. ^ "Vogalib". www.rxreasoner.com.
  12. PMID 34292534
    .
  13. PMID 5596819
    .
  14. PMID 5797645
    .
  15. PMID 5314918
    .
  16. PMID 4944444
    .
  17. PMID 4261213
    .
  18. PMID 38705
    .
  19. ^
    PMID 9193370
    .
  20. PMID 9358940
    .
  21. PMID 11283143
    .
  22. S2CID 24370010
    .
  23. S2CID 8708071
    .
  24. PMID 26171218
    .
  25. PMID 34918875
    .
  26. ^
    PMID 2206785
    .
  27. ^ "A Phase 2 Randomized, Double-blind, Placebo-Controlled, Parallel-Group Study, of the Safety and Efficacy of NG101 Administered Orally to Patients With Gastroparesis". clinicaltrials.gov. 4 November 2022.
  28. PMID 35926490
    .
  29. doi:10.1016/S0016-5085(16)30794-6
    .
  30. PMID 25874755
    .
  31. ^ DE 1092476, Jacob RM, Robert JG, issued 1960, assigned to Rhone Poulenc SA. 
  32. S2CID 102478746
    .

External links