Monday, May 4, 2015

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].


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.


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%).

1. DeLorenzo, C.; et. al. SEP-225289 serotonin and dopamine transporter occupancy: a PET study. J Nucl Med 2011, 52(7), 1150-1155.
2. Open-label Safety Study in Adults With ADHD. NCT02160262 (retrieved 01-05-2015)
3. Adult Attention Deficit Hyperactivity Disorder. NCT01692782 (retrieved 01-05-2015)
4. Dasotraline Pediatric ADHD Study. NCT02428088 (retrieved 01-05-2015)