Tedatioxetine

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.{{cite journal | vauthors = Frederiksen T, Areberg J, Schmidt E, Stage T, Brøsen K | title = Cytochrome P450 2D6 genotype–phenotype characterization through population pharmacokinetic modeling of tedatioxetine | journal = Chembiochem : a European Journal of Chemical Biology | volume = 22 | issue = 17 | pages = 2711–2720 | date = Sep 2021 | pmid = 34107164 | doi = 10.1002/psp4.12663 }}

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.

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

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-HT_2A, 5-HT_2C, and 5-HT₃ serotonin receptors and α_1A-adrenergic receptor antagonist, potentially enhancing monoamine transmission and reducing side effects like nausea associated with 5-HT₃ activation.{{cite web | title = Tedatioxetine (Lu AA24530) | url = https://www.medchemexpress.com/Tedatioxetine.html | website = MedChemExpress | access-date = 17 June 2025 }}{{cite patent | title = 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 | number = 2010144788 | country = US | pubdate = 10 June 2010 | inventor = Stensbol TB, Miller S | assign1 = H Lundbeck AS }}{{cite book | vauthors = Stahl SM | title = Depression and bipolar disorder: Stahl's essential psychopharmacology | pages = 206 | date = 19 May 2008 | url = https://books.google.com/books?id=zqvVZOea2JAC&pg=PA206 | publisher = Cambridge University Press | isbn = 978-0-521-88663-5 | access-date = 22 November 2011 }}{{cite book | vauthors = Stolerman IP | title = Encyclopedia of Psychopharmacology | pages = 105 | date = 30 August 2010 | url = https://books.google.com/books?id=qoyYobgX0uwC&pg=PA105 | publisher = Springer | isbn = 978-3-540-68698-9 | access-date = 22 November 2011 }}{{cite web | title = Lu AA24530 shows positive results in major depressive disorder phase II study | date = 2 July 2009 | url = http://www.fiercebiotech.com/press-releases/lu-aa24530-shows-positive-results-major-depressive-disorder-phase-ii-study | work = FierceBiotech | access-date = 9 March 2010 | archive-date = 20 April 2012 | archive-url = https://web.archive.org/web/20120420101656/http://www.fiercebiotech.com/press-releases/lu-aa24530-shows-positive-results-major-depressive-disorder-phase-ii-study | url-status = live }}

Preclinical studies suggest this profile may improve efficacy in MDD by targeting multiple neurotransmitter systems.{{cite news | title = Tedatioxetine (Major Depressive Disorder) - Forecast and Market Analysis to 2023 | date = 24 June 2014 | url = https://www.prnewswire.com/news-releases/tedatioxetine-major-depressive-disorder---forecast-and-market-analysis-to-2023-265246251.html | work = PRNewswire | access-date = 17 June 2025 }}

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.{{cite journal | vauthors = Javelot H | title = Psychopharmacology of anxiety and depression: Historical aspects, current treatments and perspectives | journal = Trends in Biochemical Sciences | volume = 40 | issue = 11 | pages = 648–661 | date = Nov 2015 | pmid = 26481500 | pmc = 4630146 | doi = 10.1016/j.pharma.2015.09.002 }}

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. 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.{{cite web | title = Tedatioxetine | date = 20 October 2016 | url = https://go.drugbank.com/drugs/DB12689 | website = DrugBank Online | access-date = 17 June 2025 | archive-date = 3 December 2023 | archive-url = https://web.archive.org/web/20231203093608/https://go.drugbank.com/drugs/DB12689 | url-status = live }}

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.{{cite web | title = Tedatioxetine Revisited | date = 3 October 2016 | url = https://newdrugapprovals.org/2016/10/03/tedatioxetine/ | website = New Drug Approvals | access-date = 17 June 2025 }} The discontinuation reflects the competitive MDD market, with patent expiries for drugs like Cymbalta and Abilify and the launch of vortioxetine in 2014.{{Cite patent | title = Compound for preparing 4-(2-(4-methylphenylthio))phenylpiperidine, and preparation method and use thereof | number = 2015090160 | country = WO | pubdate = 2015-06-25 | assign = NHWA Pharma Corp. | invento = Cao L, Xin J, Yang X }}

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.

• MIN-117
• TGBA01AD
• Vilazodone
• Vortioxetine
• Triple reuptake inhibitor
• Major depressive disorder
• Generalized anxiety disorder
• CYP2D6
• Serotonin receptor antagonist

{{Reflist}}

• [http://hugin.info/130085/R/1326803/312416.pdf Lu AA24530 shows positive results in major depressive disorder phase II study]
• [https://pubchem.ncbi.nlm.nih.gov/compound/9878913 PubChem – Tedatioxetine]
• [https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:177771 ChEBI – Tedatioxetine]
• [https://go.drugbank.com/drugs/DB12689 DrugBank – Tedatioxetine]

{{Antidepressants}}

{{Adrenergic receptor modulators}}

{{Monoamine reuptake inhibitors}}

{{Serotonin receptor modulators}}

Category:4-Piperidinyl compounds

Category:Abandoned drugs

Category:Antidepressants

Category:Thioethers