Tedatioxetine

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

Clinical data
Other names	Lu AA24530; Lu-AA-24530
ATC code	none
Legal status
Legal status	Investigational
Identifiers
IUPAC name 4-{{#parsoidfragment:2}}{2-[(4-methylphenyl)sulfanyl]phenyl}piperidine
CAS Number	508233-95-2 Y
PubChem CID	9878913
ChemSpider	8054590 Y
UNII	5H681S8O3S
KEGG	D10170 N
CompTox Dashboard (EPA)	DTXSID801029350
Chemical and physical data
Formula	C18H21NS
Molar mass	283.43 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C=C1)=CC=C1SC2=C(C3CCNCC3)C=CC=C2
InChI InChI=1S/C18H21NS/c1-14-6-8-16(9-7-14)20-18-5-3-2-4-17(18)15-10-12-19-13-11-15/h2-9,15,19H,10-13H2,1H3 Y Key:CVASBKDYSQKLSO-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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-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.^{[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

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