Vortioxetine | Antidepressant | Treatment for Major Depressive Disorder | Treatment for Generalized Anxiety Disorder | SERT Inhibitior | 5-HT Receptor Modulator

Vortioxetine [1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine] is an orally administered small molecule developed as once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). As a drug, Vortioxetine is a bis-aryl-sulphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation.

Vortioxetine: 2D and 3D Structure

Vortioxetine binds to the human serotonin (5-HT) transporter (SERT) with high affinity (K_i = 1.6 nM) and is a potent inhibitor of serotonin reuptake (IC₅₀ = 5.4 nM), whereas its affinity for transporters of noradrenaline (K_i = 113 nM) and dopamine (K_i greater than 1000 nM) is much lower or negligible. The drug also has a broad receptor-binding profile, binding to the 5-HT1A receptor (K_i = 15 nM) where it acts as an agonist, the 5-HT1B receptor (K_i = 33 nM) where it acts as a partial agonist, and the 5-HT1D, 5-HT3 and 5-HT7 receptors (K_i = 54, 3.7 and 19 nM, respectively) where it displays antagonistic properties [1, 2].

Animal and in vitro studies indicate that several neurotransmitter systems may be impacted by vortioxetine, with the drug enhancing levels of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in certain areas of the brain, as well as modulating γ-aminobutyric acid and glutamate neurotransmission. Results from additional animal models suggest vortioxetine may also improve measures of cognitive function, such as memory. In healthy volunteers, single or repeated administration of vortioxetine (10 mg) did not impair cognitive function, psychomotor performance or driving ability in a placebo-controlled study.

In September 2013, Vortioxetine was approved as Brintellix for the once-daily treatment of adults with MDD in the USA and one month later, EMA approved it as it first in line treatment for Europeans with MDD. It is marketed as Trintellix in Canada.

Vortioxetine was discovered by scientists at Lundbeck, where it was known as Lu AA21004. Takeda and Lundbeck entered into a strategic alliance to co-develop and co-commercialise vortioxetine and tedatioxetine in Japan and the USA in September 2007. The two companies will jointly complete product development, which will be funded primarily by Takeda, and the companies will share revenue generated in the USA and Japan.

Vortioxetine is administered orally at a starting dosage of 10 mg/day, with the dosage increased to 20 mg/day, as tolerated; 5 mg/ day may be considered if higher dosages are not tolerated. Dosages greater than 20 mg/day have not been assessed for efficacy or safety in controlled trials.

Vortioxetine Synthesis

WO2007144005A1: Industrial process 

J Med Chem 2011, 54(9), 3206-3221: (also see Ref. 3; it has same details)

Identifications:

Sideeffects:

Tolerability data from three 52-week, open-label, extension studies (NCT00694304, NCT00707980 and NCT01323478) comprising of patients taking vortioxetine (2.5-20 mg/day) confirm that greater than 70% of patients experienced adverse events (AEs). The most frequent (greater than 10% occurrence) being nausea, headache, nasopharyngitis and dizziness; where reported, sexual dysfunction adverse events were uncommon. 

Serious adverse events occurred in some patients, with those considered to be vortioxetine related including left hemispheric ischaemic stroke, tachycardia (paroxysmal and supraventricular), depression and major depression.

Moreover, some patients who abruptly discontinue vortioxetine 15 or 20 mg/day may experience symptoms such as mood swings, sudden outburst of anger, headache, dizziness, muscle tension or runny nose within the first week post discontinuation.

References:

1. Gibb, A.; et. al. Vortioxetine: first global approval. Drugs 2014, 74(1), 135-145.

2. Bang-Andersen, B.; et. al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011, 54(9), 3206-3221.

3. Bang-Andersen, B.; et. al. 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment WO2007144005A1

Drugs in Clinical Pipeline: Dasotraline | Treatment of ADHD | Triple Reuptake Inhibitor | Treatment of Attention Deficit Hyperactivity Disorder

Dasotraline [(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine] is a new serotonin  [5-hydroxytryptamine (5-HT)], dopamine (DA) and norepinephrine (NE) reuptake inhibitor (SDNRI), which blocks pre-synaptic dopamine transporters to increase their levels in the brain. For this unique three sided attack, it is a so-called a triple reuptake inhibitor (TRI). Triple reuptake inhibitors represent a potential new class of antidepressant drugs that block norepinephrine, dopamine and serotonin transporters.

Dasotraline: 2D and 3D Structure

Dasotraline is an antidepressant which had been in early clinical trials at Sepracor (now Sunovion Pharmaceuticals) for the treatment of major depressive disorder (MDD). In 2010, the company discontinued development of the compound for this indication. At present, phase II clinical trials are under way for the treatment of attention deficit/hyperactivity disorder (ADHD). In preclinical studies, the drug has been shown to be a potent and balanced reuptake inhibitor of serotonin, norepinephrine and dopamine. A drug candidate with a triple mechanism of action as such may provide a broader spectrum of therapy than currently marketed antidepressants. Sunovion has also planned clinical trials to evaluate the drug’s safety and usefulness in treating children with ADHD.

Common Name: Dasotraline

Synonyms:  SEP-225289; SEP225289; SEP 225289

IUPAC Name: (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine

CAS Number: 675126-05-3

Mechanism of Action: Triple Reuptake Inhibitor

Indication: Treatment of Attention Deficit Hyperactivity Disorder; Treatment of ADHD

Development Stage: Phase I/II

Company: Sunovion Pharmaceuticals

1H NMR (Estimated) for Dasotraline

Early Study

The double-blind clinical trial ran for four weeks, and measured symptoms against the ADHD Rating Scale-IV, which tracks the frequency of DSM-IV criteria like hyperactivity, impulsivity, and inattentiveness. The ADHD adults who participated were randomly assigned doses of 4 mg/daily, 8 mg/daily, or a placebo. The results showed a significant improvement in symptoms for the 8 mg dosage, and some improvement with the 4 mg dosage. Some participants experienced side effects, including insomnia, anxiety, and panic attacks.

PET Study

SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy [1].

Methodology

Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2ß-carbomethoxy-3ß-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events.

Results

Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC₅₀ was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%).

References:

1. DeLorenzo, C.; et. al. SEP-225289 serotonin and dopamine transporter occupancy: a PET study. J Nucl Med 2011, 52(7), 1150-1155.

2. ClinicalTrials.gov Open-label Safety Study in Adults With ADHD. NCT02160262 (retrieved 01-05-2015)

3. ClinicalTrials.gov Adult Attention Deficit Hyperactivity Disorder. NCT01692782 (retrieved 01-05-2015)

4. ClinicalTrials.gov Dasotraline Pediatric ADHD Study. NCT02428088 (retrieved 01-05-2015)