Chemistry:Tedatioxetine

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Tedatioxetine (developmental code name Lu AA24530) is an experimental antidepressant developed by H. Lundbeck A/S for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). It acts as a triple reuptake inhibitor (TRI) with preference for serotonin and norepinephrine over dopamine, and as an antagonist at 5-HT2A, 5-HT2C, 5-HT3, and α1A-adrenergic receptors. In 2007 Lundbeck and Takeda entered into a partnership that included tedatioxetine but was focused on another, more advanced Lundbeck drug candidate, vortioxetine.[1]

Tedatioxetine reached Phase II clinical trials for major depressive disorder in 2009 but was discontinued in May 2016, with no further development reported. Despite its termination, data from clinical studies have provided valuable insights into CYP2D6 metabolism and pharmacogenetics.[2][3][4][5]

Pharmacology

Pharmacokinetics

Tedatioxetine is a sensitive substrate of the CYP2D6 enzyme, exhibiting significant interindividual variability in metabolism due to genetic polymorphisms. A 2021 population pharmacokinetic (popPK) study involving 578 subjects quantified CYP2D6 activity across genotypes, reporting mean oral clearances of 18 L/h for poor metabolizers (PMs), 40 L/h for intermediate metabolizers (IMs), 60 L/h for normal metabolizers (NMs), and 77 L/h for ultrarapid metabolizers (UMs). Approximately 80% of clearance is mediated by CYP2D6.[6]

The drug has a slow absorption rate, with a median time to maximum plasma concentration (tmax) of 5–6 hours. Its primary metabolite, Lu AA37208, shows a similar or shorter tmax, indicating presystemic metabolism. The study highlighted low enzyme activity for CYP2D6*17 and *41 alleles, suggesting a need to revise activity scores for personalized dosing.[6]

CYP2D6 variability posed challenges for consistent dosing across populations, particularly for CYP2D6*17 and *41 carriers.[6]

Pharmacodynamics

Tedatioxetine is a multimodal antidepressant that inhibits the reuptake of serotonin, norepinephrine, and dopamine, with a preference for serotonin and norepinephrine (5-HT > NE > DA). It also antagonizes 5-HT2A, 5-HT2C, and 5-HT3 serotonin receptors and α1A-adrenergic receptor antagonist, potentially enhancing monoamine transmission and reducing side effects like nausea associated with 5-HT3 activation.[7][8][9][10][11]

Preclinical studies suggest this profile may improve efficacy in MDD by targeting multiple neurotransmitter systems.[12]

The compound’s receptor antagonism, particularly at 5-HT2C and 5-HT3, may contribute to its anxiolytic properties, making it a candidate for GAD treatment. Its triple reuptake inhibition distinguishes it from selective serotonin reuptake inhibitors (SSRIs), potentially offering broader symptom relief in complex mood disorders.[13]

Clinical development

Tedatioxetine was discovered by Lundbeck and entered a partnership with Takeda Pharmaceutical Company in 2007, alongside the more advanced candidate vortioxetine. By 2009, tedatioxetine had progressed to Phase II clinical trials for MDD, demonstrating promising efficacy and safety in preliminary studies.[2] However, Lundbeck and Takeda prioritized vortioxetine, which gained regulatory approval, leading to tedatioxetine’s removal from Lundbeck’s pipeline by August 2013. On 10 May 2016, all development was officially discontinued.[14]

A Chinese patent (WO 2009109541) indicates interest in tedatioxetine’s synthesis outside Lundbeck, suggesting potential for further research, though no active development has been reported.[15] The discontinuation reflects the competitive MDD market, with patent expiries for drugs like Cymbalta and Abilify and the launch of vortioxetine in 2014.[12][16]

Synthesis

Tedatioxetine’s synthesis, as described in patents (WO 2003/029232, WO 2009109541), involves challenges with low yield and purification difficulties. Early methods required hazardous reagents like butyl lithium and low-temperature reactions, limiting industrial scalability. Improved routes replaced benzyl with Boc-protecting groups and used trifluoroacetic acid (TFA) and triethylsilane for dehydroxylation, but high-cost starting materials (e.g., 2-bromobenzene, palladium catalysts) and safety concerns persisted.[15]

See also

References

  1. ↑ "Lundbeck, Takeda enter strategic alliance for mood disorder, anxiety drugs"]. First Word Pharma. 5 September 2007. http://www.firstwordpharma.com/node/88051?tsid=17#axzz3xkIEA5eH. 
  2. ↑ 2.0 2.1 "TEDATIOXETINE". https://drugs.ncats.io/drug/5H681S8O3S. 
  3. ↑ "Pipeline of Lundbeck". http://investor.lundbeck.com/pipeline.cfm. 
  4. ↑ "Tedatioxetine". UK Medicines Information. http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4990. 
  5. ↑ "Tedatioxetine". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800023694. 
  6. ↑ 6.0 6.1 6.2 "Cytochrome P450 2D6 genotype–phenotype characterization through population pharmacokinetic modeling of tedatioxetine". ChemBioChem 22 (17): 2711–2720. Sep 2021. doi:10.1002/psp4.12663. PMID 34107164. 
  7. ↑ "Tedatioxetine (Lu AA24530)". https://www.medchemexpress.com/Tedatioxetine.html. 
  8. ↑ Stensbol TB, Miller S, "4-[2-(4-methylphenylsulfanyd-phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of adhd, melancholia, treatment resistant depression or residual symptoms in depression", US patent 2010144788, published 10 June 2010, assigned to H Lundbeck AS
  9. ↑ Depression and bipolar disorder: Stahl's essential psychopharmacology. Cambridge University Press. 19 May 2008. pp. 206. ISBN 978-0-521-88663-5. https://books.google.com/books?id=zqvVZOea2JAC&pg=PA206. Retrieved 22 November 2011. 
  10. ↑ Encyclopedia of Psychopharmacology. Springer. 30 August 2010. pp. 105. ISBN 978-3-540-68698-9. https://books.google.com/books?id=qoyYobgX0uwC&pg=PA105. Retrieved 22 November 2011. 
  11. ↑ "Lu AA24530 shows positive results in major depressive disorder phase II study". FierceBiotech. 2 July 2009. http://www.fiercebiotech.com/press-releases/lu-aa24530-shows-positive-results-major-depressive-disorder-phase-ii-study. 
  12. ↑ 12.0 12.1 "Tedatioxetine (Major Depressive Disorder) - Forecast and Market Analysis to 2023". PRNewswire. 24 June 2014. https://www.prnewswire.com/news-releases/tedatioxetine-major-depressive-disorder---forecast-and-market-analysis-to-2023-265246251.html. 
  13. ↑ "Psychopharmacology of anxiety and depression: Historical aspects, current treatments and perspectives". Trends in Biochemical Sciences 40 (11): 648–661. Nov 2015. doi:10.1016/j.pharma.2015.09.002. PMID 26481500. 
  14. ↑ "Tedatioxetine". 20 October 2016. https://go.drugbank.com/drugs/DB12689. 
  15. ↑ 15.0 15.1 "Tedatioxetine Revisited". 3 October 2016. https://newdrugapprovals.org/2016/10/03/tedatioxetine/. 
  16. ↑ "Compound for preparing 4-(2-(4-methylphenylthio))phenylpiperidine, and preparation method and use thereof" WO patent 2015090160, published 2015-06-25



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