Agomelatine

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Structural formula
Agomelatine
General
Non-proprietary name Agomelatine
other names

N - (2- (7-methoxy-1-naphthyl) ethyl) acetamide

Molecular formula C 15 H 17 NO 2
External identifiers / databases
CAS number 138112-76-2
EC number 629-727-7
ECHA InfoCard 100.157.896
PubChem 82148
ChemSpider 74141
DrugBank DB06594
Wikidata Q395229
Drug information
ATC code

N06 AX22

Drug class

Antidepressants

properties
Molar mass 243.30 g · mol -1
Physical state

firmly

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
09 - Dangerous for the environment

Caution

H and P phrases H: 400
P: 273
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Agomelatine (trade name Valdoxan; manufacturer Servier ) is a chemical compound structurally related to melatonin . The drug from the group of antidepressants is used in the treatment of major depression in adults.

Chemical structure

Agomelatine is a metabolically stable analogue of melatonin with a high affinity for the melatonin receptors. In contrast to melatonin, the bicyclic aromatic molecular structure contains a benzene ring instead of the heterocyclic pyrrole ring and can therefore not be derived from indole , but from naphthalene .

presentation

Agomelatine was first used in 1992 by Yous et al. in a three-step synthesis based on the difficult to access (2-methoxynaphthalen-8-yl) acetic acid . (2-Methoxynaphthalen-8-yl) acetic acid itself can be prepared from 7-methoxy-3,4-dihydro-2 H -naphthalen-1-one . In addition, a number of patents have appeared that describe the route in question in a modified form.

In February 2010, Servier published two patents on new agomelatine syntheses. The feature of the two new routes was that the laborious construction of the naphthalene structure through the use of 2,8-substituted naphthalene derivatives was avoided. The most attractive of the two is a three-step synthesis, starting from the long-known (2-methoxynaphthalen-8-yl) oxoacetic acid.

In 2011, Markl et al. Described that said patent route did not lead to the product described. At the same time, they published their own four-step agomelatine route, also starting from (2-methoxynaphthalen-8-yl) oxoacetic acid. The route includes the borane reduction of the oxoacetic acid, dehydration of the diol obtained to the aldehyde, the conversion to the aldoxime using hydroxylamine hydrochloride and the final Raney nickel hydrogenation / acetylation to obtain agomelatine. The final step of in-situ - hydrogenation / acetylation an aldoxime was previously unknown.

pharmacology

Agomelatine is a novel approach to antidepressant treatment. Agomelatine acts agonistically on the melatonergic MT 1 and MT 2 receptors and antagonistically on the 5HT 2C receptors in the suprachiasmatic nucleus and in this way can influence the "internal clock" of humans and resynchronize circadian rhythms . The antidepressant effect of agomelatine cannot be attributed solely to the melatonergic component or the antagonism at the 5HT 2C receptor. Rather, the interaction of both effects is responsible for this. This is because the antagonistic effect on the 5HT 2C receptors leads to a blockade of the stimulating and therefore undesirable effect of serotonin in the suprachiasmatic nucleus (SCN) in the evening and thus intensifies the melatonin-agonistic effect. In addition, the 5HT 2C receptor blockade indirectly mediates an increase in norepinephrine and dopamine in the frontal cortex , which in itself has an antidepressant effect. The antagonism at the 5HT 2C also increases deep sleep and thus improves the quality of sleep and consequently the daily vigilance .

Clinical trial

Study situation

The antidepressant effect of agomelatine was examined in several large, placebo-controlled studies as part of the approval process (see below). Six studies were carried out on the short-term effectiveness of agomelatine, including a dose-finding study with three different dose groups. In two of the six-week studies and in the patients who received 25 mg agomelatine daily in the dose-finding study, there was a significant difference in effectiveness compared to placebo. Another study had negative results; in two studies, both agomelatine and the reference substances ( paroxetine , fluoxetine ) did not differ significantly from placebo. These studies have not yet been published.

In a further four randomized controlled studies , agomelatine was compared with other antidepressants with regard to effectiveness, sleep quality and tolerability (comparative studies vs. fluoxetine, venlafaxine and sertraline ). Agomelatine showed an equally effective antidepressant effectiveness both in comparison with fluoxetine (here effectiveness of the primary target parameters) and in comparison with venlafaxine and sertraline (here effectiveness of secondary target parameters). The majority of these studies included outpatients with a moderate to severe depressive episode. The effectiveness of agomelatine in improving subjective sleep was compared to venlafaxine and to sertraline using the LSEQ (Leeds Sleep Rating Questionnaire). In the study vs. Venlafaxine was shown to be superior to agomelatine in terms of getting to sleep and in terms of sleep quality as early as week 1 (p <0.01 and p <0.05). The difference remained significant throughout the 6 weeks of treatment (p <0.01 and p <0.05, respectively). There was also a significant difference in favor of agomelatine with regard to the ease of awakening from week 2 (p <0.05) and the coordination of behavioral patterns after awakening (“integrity of behavior after awakening “) With a significant difference after week 1 (p <0.0001) and at the endpoint of the study (p <0.05) compared to venlafaxine. This may not come as a surprise, as insomnia has been described as a common adverse effect of venlafaxine; However, it is worth mentioning here that agomelatine, as a non-drive-increasing substance, was significantly superior to the drive-increasing venlafaxine in terms of parameters such as activity on the day after week 1 and was comparable over the course of 6 weeks. In the study vs. Sertraline showed a significant difference in terms of getting to sleep and the quality of sleep in favor of agomelatine after week 2 (p <0.001 and p <0.05), but not at the end of the study. The relative amplitude of the circadian rest-activity rhythm improved significantly compared to sertraline, which can be seen as a normalization of the circadian rhythm.

A first long-term study over 34 (up to 52) weeks could not show any significant difference between agomelatine and placebo. In a second, six-month relapse prevention study, patients who switched from agomelatine to placebo after an initial response had significantly more relapses after six months (46.6%) than those who continued to take agomelatine (21.7% relapses) .

compatibility

In the clinical studies, agomelatine was well tolerated and the side effects were on a level with placebo. Typical side effects of other antidepressants, such as loss of libido , erectile dysfunction and weight gain, were significantly less common with agomelatine than with the active comparator substances. Since less than 1.1% of the patients treated with agomelatine vs. 0.7% of the patients treated with placebo had increased AST and / or ALT values ​​(> 3 times the upper normal range) should be checked regularly at the start of therapy, after 6, 12 and 24 weeks and thereafter, if clinically indicated required. Impaired liver function, as in liver cirrhosis or active liver disease, is a contraindication. In October 2012, the manufacturer Servier - in coordination with the European Medicines Agency - sent out an information leaflet for healthcare professionals to explain the importance of liver function checks in patients who use agomelatine. to remember. After abrupt discontinuation of treatment, agomelatine did not induce withdrawal symptoms .

Admission process and future

The brand name Valdoxan was registered in April 2005 by the French manufacturer Servier . Where an application was rejected in 2006 after the Committee for Medicinal Products (Committee for Medicinal Products for Human Use, CHMP) could see no sufficient antidepressant effect of the European Medicines Agency of the submitted about music. After submission of further study documents the granted European Commission the company Les Laboratoires Servier on 19 February 2009, the marketing authorization of Valdoxan throughout the European Union.

Servier had licensed the rights to agomelatine to Novartis for the USA and other countries . Novartis then started several new clinical studies with the substance; has since stopped research. Agomelatine has also been available as a generic ( Zilbea Zentiva ) (Agomaval (TAD Pharma)) since 2019 .

Web links

Individual evidence

  1. ↑ a b Agomelatine data sheet from Sigma-Aldrich , accessed on May 5, 2011 ( PDF ).
  2. ↑ a b c Specialist information Valdoxan (PDF; 88 kB) on Fachinfo-Service.
  3. ^ S. Yous, J. Andrieux, HE Howell, PJ Morgan, P. Renard, B. Pfeiffer, D. Lesieur, B. Guardiola-Lemaitre: Novel naphthalenic ligands with high affinity for the melatonin receptor . In: J. Med. Chem. . 35, No. 8, 1992, pp. 1484-1486. doi : 10.1021 / jm00086a018 .
  4. ↑ Process for the synthesis of agomelatine .
  5. ^ Christian Markl, Darius Zlotos: A Novel Synthesis of the Antidepressant Agomelatine. In: Synthesis. 2011, 2011, p. 79, doi: 10.1055 / s-0030-1258968 .
  6. ↑ Audinot, V., F. Mailliet, et al. (2003). New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmiedeberg's Archives of Pharmacology 367: 553-561. PMID 12764576
  7. ↑ San, L. Arranz, B (2008). Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system. Eur Psychiatry 23 (6): 396-402, PMID 18583104 .
  8. ↑ Millan, MJ, A. Gobert, et al. (2003). The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 306 (3): 954-964, PMID 12750432 .
  9. ↑ Loo H et al., In: Int Clin Psychopharmacol . 2002; 17: 239-247, PMID 12177586 .
  10. ^ Kennedy SH, Emsley R, Europ. Neuropsychopharmacol 2006; 16: 93-100, PMID 16249073 .
  11. ↑ Olié JP, Kasper S, Int. J. Neuropsychopharmacol 2007; 10 (5): 661-73, PMID 17477888 .
  12. ↑ a b Refusal CHMP Assessment Report for Valdoxan (Agomelatine) (PDF; 683 kB); European Medicines Agency, July 27, 2006.
  13. ↑ Hale, A., R. Corral, et al. (2010). Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study. Int Clin Psychopharmacol e-pub ahead of print, PMID 20856123 .
  14. ↑ a b c d Lemoine, P., C. Guilleminault, et al. (2007). "Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine." J Clin Psychiatry 68 (11): 1723-1732, PMID 18052566 .
  15. ↑ Kennedy, SH, S. Rizvi, et al. (2008). A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol 28 (3): 329-333, PMID 18480691 .
  16. ↑ a b c d Kasper, S., G. Hajak, et al. (2010). "Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline." J Clin Psychiatry 71 (2): 109-120, PMID 20193645 .
  17. ↑ Goodwin, GM, R. Emsley, et al. (2009). Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 70 (8): 1128-1137, PMID 19689920 .
  18. ↑ Medicines Commission of the German Medical Association: Active substance AKTUELL 5/2010 (PDF; 89 kB).
  19. ↑ Information for healthcare professionals regarding the risk of hepatotoxicity with agomelatine (Valdoxan / Thymanax). (PDF; 152 kB) Retrieved October 15, 2012 .
  20. ↑ Montgomery SA et al., Int Clin Psychopharmacol. 2004 Sep; 19 (5): 271-280, PMID 15289700 .
  21. ↑ Questions and Answers on Recommendation for Refusal of Marketing Authorization for VALDOXAN / THYMANAX (PDF; 41 kB) - European Medicines Agency, November 18, 2006.
  22. ↑ COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE SUMMARY OF POSITIVE OPINION for VALDOXAN ( Memento of October 7, 2009 in the Internet Archive ) (PDF; 36 kB).
  23. ↑ Servier and Novartis sign licensing agreement for agomelatine ; Message from Servier, PMID 18457470 .
  24. ↑ ClinicalTrials.gov: Studies with the active ingredient agomelatine .
  25. ↑ Srip intelligence: Novartis drops future blockbuster agomelatine ( Memento from August 8, 2017 in the Internet Archive ) .