Esmirtazapine (original) (raw)

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Drug formerly under development for treatment of menopause symptoms

Pharmaceutical compound

Esmirtazapine
Clinical data
Routes of administration Oral
ATC code none
Legal status
Legal status In general: uncontrolled
Pharmacokinetic data
Metabolism Liver (CYP2D6)[2]
Elimination half-life 10 hours[1]
Identifiers
IUPAC name (S)-1,2,3,4,10,14b-hexahydro-2-methylpyrazino(2,1-a)pyrido(2,3-c)(2)benzazepine
CAS Number 61337-87-9 checkY
PubChem CID 3085218E. maleate: 6451144
DrugBank DB06678 ☒N
ChemSpider 2342166 checkY
UNII 4685R51V7M
KEGG D04055 checkY
CompTox Dashboard (EPA) DTXSID001029320 Edit this at Wikidata
ECHA InfoCard 100.056.994 Edit this at Wikidata
Chemical and physical data
Formula C17H19N3
Molar mass 265.360 g·mol−1
3D model (JSmol) Interactive image
Melting point 114 to 116 °C (237 to 241 °F)
Solubility in water Soluble in methanol and chloroform
SMILES CN1CCN2c3c(cccn3)Cc4ccccc4[C@H]2C1
InChI InChI=1S/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3/t16-/m1/s1 checkYKey:RONZAEMNMFQXRA-MRXNPFEDSA-N checkY
☒NcheckY (what is this?) (verify)

Esmirtazapine (ORG-50,081) is a tetracyclic antidepressant drug that was under development by Organon for the treatment of insomnia and vasomotor symptoms (e.g., hot flashes) associated with menopause.[3][4][5][6] Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine and possesses similar overall pharmacology, including inverse agonist actions at H1 and 5-HT2 receptors and antagonist actions at α2-adrenergic receptors.[3][7]

Notably, esmirtazapine has a shorter half life of around 10 hours, compared to R-mirtazapine and racemic mixture, which has a half-life of 18–40 hours.[1] Merck has run several studies on low dose (3–4.5 mg) esmirtazapine for the treatment of insomnia. It is attractive for treating insomnia since it is a potent H1-inhibitor and a 5-HT2A antagonist.[8][1] Unlike low-dose mirtazapine, the half life (10 hours) is short enough that next-day sedation may be manageable, however, for people with CYP2D6 polymorphisms, which constitute a sizable fraction of the population, the half-life is expected to be quite a bit longer. Merck researchers claimed that the incidence of next-day sedation was not a problem in one of their studies, but this claim has been challenged (15% of patients complained of daytime sleepiness vs 3.5% in the placebo group).[9]

In March 2010, Merck terminated its internal clinical development program for esmirtazapine for hot flashes and insomnia, "for strategic reasons".[10]

  1. ^ a b c Ruwe F, IJzerman-Boon P, Roth T, Zammit G, Ivgy-May N (October 2016). "A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia". Journal of Clinical Psychopharmacology. 36 (5): 457–464. doi:10.1097/JCP.0000000000000546. PMID 27482970. S2CID 25639396.
  2. ^ Lillin-de Vries O, Kerbusch T, de Kam PJ, Ivgy-May N, Bursi R. "A population analysis on the effects of the CYP2D6 deficiency on pharmacokinetics and exposure of esmirtazapine in healthy volunteers" (PDF). Oss, The Netherlands: Schering-Plough Corporation.
  3. ^ a b "Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD". Neurotransmitter.net.
  4. ^ Clinical trial number NCT00561574 for "A Long-Term Safety Study of Org 50081 in Elderly Outpatients With Chronic Primary Insomnia (176005)" at ClinicalTrials.gov
  5. ^ Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia". Current Topics in Medicinal Chemistry. 8 (11): 969–976. doi:10.2174/156802608784936700. PMID 18673166.
  6. ^ Lewis V (November 2009). "Undertreatment of menopausal symptoms and novel options for comprehensive management". Current Medical Research and Opinion. 25 (11): 2689–2698. doi:10.1185/03007990903240519. PMID 19775194. S2CID 206964530.
  7. ^ Stahl SM (2008). "Antidepresents". Depression and bipolar disorder: Stahl's essential psychopharmacology (3rd ed.). Cambridge, UK: Cambridge University Press. ISBN 978-0-521-88663-5.
  8. ^ Ivgy-May N, Ruwe F, Krystal A, Roth T (July 2015). "Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial". Sleep Medicine. 16 (7): 838–844. doi:10.1016/j.sleep.2015.04.001. PMID 26047892.
  9. ^ Ivgy-May N, Hajak G, van Osta G, Braat S, Chang Q, Roth T (September 2020). "Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension". Journal of Clinical Sleep Medicine. 16 (9): 1455–1467. doi:10.5664/jcsm.8526. PMC 7970588. PMID 32351205.
  10. ^ "Form 10-K" (PDF). Merck & Co., Inc. Archived from the original (PDF) on 2011-08-05. Retrieved 2011-05-03.