Tedatioxetine reachedPhase II clinical trials formajor 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 intoCYP2D6 metabolism andpharmacogenetics.[2][3][4][5]
Tedatioxetine is a sensitive substrate of theCYP2D6 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]
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 antagonizes5-HT2A,5-HT2C, and5-HT3 serotonin receptors andα1A-adrenergic receptorantagonist, potentially enhancing monoamine transmission and reducing side effects like nausea associated with5-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]
Tedatioxetine was discovered by Lundbeck and entered a partnership withTakeda Pharmaceutical Company in 2007, alongside the more advanced candidatevortioxetine. 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 likeCymbalta andAbilify and the launch of vortioxetine in 2014.[12][16]
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]
^US 2010144788, 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", published 10 June 2010, assigned to H Lundbeck AS
^WO 2015090160, "Compound for preparing 4-(2-(4-methylphenylthio))phenylpiperidine, and preparation method and use thereof", published 2015-06-25, assigned to NHWA Pharma Corp.
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