Ulotaront

Last updated
Ulotaront
SEP-363856.svg
Clinical data
Other namesSEP-363856; SEP363856; SEP-856; SEP856
Identifiers
  • 1-[(7S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]-N-methylmethanamine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C9H13NOS
Molar mass 183.27 g·mol−1
3D model (JSmol)
  • CNC[C@H]1C2=C(CCO1)C=CS2
  • InChI=1S/C9H13NOS/c1-10-6-8-9-7(2-4-11-8)3-5-12-9/h3,5,8,10H,2,4,6H2,1H3/t8-/m0/s1
  • Key:ABDDQTDRAHXHOC-QMMMGPOBSA-N

Ulotaront (INN Tooltip International Nonproprietary Name; [1] developmental codes SEP-363856, SEP-856) is an investigational antipsychotic that is undergoing clinical trials for the treatment of schizophrenia and Parkinson's disease psychosis. [2] [3] The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals [2] (which was subsequently merged into Sumitomo Pharma [4] ) using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube. [5]

Contents

Ulotaront is in phase III clinical trial for schizophrenia, phase II/III for generalised anxiety disorder and major depressive disorder and discontinued for narcolepsy and psychotic disorders. [6]

Research has shown that ulotaront results in a greater reduction from baseline in the PANSS total score than placebo. [7] Treatment with ulotaront, as compared with placebo, was also associated with an improvement in sleep quality. [7] Ulotaront was awarded a Breakthrough Therapy designation due to its increased efficacy and greatly reduced side effects compared to current treatments. [8]

Adverse effects

The adverse effect profile of ulotaront differs from that of other antipsychotics because its mechanism of action does not involve antagonism of dopamine receptors in the brain, which is responsible for the drug-induced movement disorders (like akathisia) that may occur with those agents. [9] Some adverse events reported in preliminary clinical trials are somnolence, agitation, nausea, diarrhea, and dyspepsia. [9]

Pharmacology

Pharmacodynamics

The mechanism of action of ulotaront in the treatment of schizophrenia is unclear. However, it is thought to be an agonist at the trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptors. [2] [10] This mechanism of action is unique among available antipsychotics, which generally antagonize dopamine receptors (especially dopamine D2 receptor). [11] [12]

Ulotaront is a full agonist of the human TAAR1 with an EC50 Tooltip half-maximal effective concentration of 140 nM and an Emax Tooltip maximal efficacy of 101.3%. [12] It is also a partial agonist of the serotonin 5-HT1A receptor (EC50 = 2,300 nM; Emax = 74.7%) and of the serotonin 5-HT1D receptor (EC50 = 262 nM; Emax = 57.1%). [12] Conversely, its activities at various other targets, such as various other serotonin receptors as well as adrenergic and dopamine receptors, are much less potent. [12]

Ulotaront decreases basal locomotor activity in rodents and this effect was absent in TAAR1 knockout mice. [13] It prevented the hyperlocomotion induced by the NMDA receptor antagonist phencyclidine (PCP). [13] [14] [12] Conversely, ulotaront did not affect dextroamphetamine-induced hyperlocomotion. [13] [14] Similarly, it did not reverse apomorphine-induced climbing behavior. [13]

Pharmacokinetics

The precise pharmacokinetic profile of ulotaront has not been reported, though the developer has suggested that the pharmacokinetic data supports once daily dosing. [10]

Research

As of 2018, Sunovion, the maker of another antipsychotic called lurasidone (Latuda), is conducting clinical trials on ulotaront in partnership with the preclinical research company PsychoGenics. [3] [15] [16] The U.S. Food and Drug Administration has granted ulotaront the breakthrough therapy designation. [10] [17] In addition to schizophrenia, ulotaront is also being studied for the treatment of psychosis associated with Parkinson's disease. [17]

The Brief Negative Symptom Scale (BNSS) has been used to assess the effect of Ulotaront on the negative symptoms of schizophrenia. [18]

In July 2023, the pharmaceutical company behind the drug announced that the drug had failed to outperform placebo in the treatment of acutely psychotic patients with schizophrenia, as measured by the PANSS. [19]

See also

Related Research Articles

<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.

<span class="mw-page-title-main">Aripiprazole</span> Atypical antipsychotic

Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as an add-on treatment for major depressive disorder and tic disorders. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Amisulpride</span> Atypical antipsychotic and antiemetic medication

Amisulpride, sold under the brand names Solian and Barhemsys, is a medication used in the treatment of schizophrenia, acute psychotic episodes, depression, and nausea and vomiting. It is specifically used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; at low doses by mouth to treat depression; and at higher doses by mouth to treat psychosis.

Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors, are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerable interest in academic and proprietary pharmaceutical research due to its role as the endogenous receptor for the trace amines phenethylamine, tyramine, and tryptamine – metabolic derivatives of the amino acids phenylalanine, tyrosine and tryptophan, respectively – ephedrine, as well as the synthetic psychostimulants, amphetamine, methamphetamine and methylenedioxymethamphetamine. In 2004, it was shown that mammalian TAAR1 is also a receptor for thyronamines, decarboxylated and deiodinated relatives of thyroid hormones. TAAR2–TAAR9 function as olfactory receptors for volatile amine odorants in vertebrates.

<span class="mw-page-title-main">Molindone</span> Antipsychotic medication

Molindone, sold under the brand name Moban, is an antipsychotic medication which is used in the United States in the treatment of schizophrenia. It is taken by mouth.

<span class="mw-page-title-main">Iloperidone</span> Atypical antipsychotic medication

Iloperidone, sold under the brand name Fanapt among others, is an atypical antipsychotic for the treatment of schizophrenia and bipolar I disorder.

Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene.

<span class="mw-page-title-main">Perospirone</span> Atypical antipsychotic medication

Perospirone (Lullan) is an atypical antipsychotic of the azapirone family. It was introduced in Japan by Dainippon Sumitomo Pharma in 2001 for the treatment of schizophrenia and acute cases of bipolar mania.

<span class="mw-page-title-main">Pimavanserin</span> Atypical antipsychotic medication

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. It is taken by mouth.

<span class="mw-page-title-main">Dasotraline</span> Chemical compound

Dasotraline is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) that was under development by Sunovion for the treatment of attention-deficit hyperactivity disorder (ADHD) and binge eating disorder (BED). Structurally, dasotraline is a stereoisomer of desmethylsertraline (DMS), which is an active metabolite of the marketed selective serotonin reuptake inhibitor (SSRI) antidepressant sertraline (Zoloft).

<span class="mw-page-title-main">Pomaglumetad</span> Drug, used as a treatment for schizophrenia

Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.

<span class="mw-page-title-main">Tiospirone</span> Atypical antipsychotic drug

Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class. It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent to those of typical antipsychotics in clinical trials but without causing extrapyramidal side effects. However, development was halted and it was not marketed. Perospirone, another azapirone derivative with antipsychotic properties, was synthesized and assayed several years after tiospirone. It was found to be both more potent and more selective in comparison and was commercialized instead.

<span class="mw-page-title-main">Roxindole</span> Dopaminergic & serotonergic drug developed for schizophrenia treatment

Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. As a result, roxindole was further researched for the treatment of depression instead. It has also been investigated as a therapy for Parkinson's disease and prolactinoma.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia and bipolar disorder. It is also prescribed as an add-on treatment for bipolar depression and major depressive disorder. Cariprazine acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. It is a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors. It is taken by mouth. The most prevalent side effects include nausea, mild sedation, fatigue, and dizziness. At higher dosages, there is an increased risk for restlessness, insomnia, and tremors.

<span class="mw-page-title-main">Brexpiprazole</span> Atypical antipsychotic

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.

<span class="mw-page-title-main">Ralmitaront</span> Investigational antipsychotic drug

Ralmitaront is an investigational antipsychotic drug which is undergoing a clinical trial for the treatment of negative symptoms in schizophrenia and schizoaffective disorder. Another clinical trial targeting acute psychotic symptoms of schizophrenia has been terminated due to lack of efficacy. It is a partial agonist of the TAAR1. The medication is being developed by the pharmaceutical company Hoffmann-La Roche. Ralmitaront had completed phase 1 clinical trials.

<span class="mw-page-title-main">ENX-104</span> Experimental antidepressant drug

ENX-104, also known as deuterated nemonapride enantiomer, is a selective dopamine D2 and D3 receptor antagonist which is under development for the treatment of major depressive disorder. It is specifically under development for the treatment of major depressive disorder characterized by anhedonia. The drug is being developed for use at low doses to preferentially block presynaptic dopamine D2 and D3 autoreceptors and hence to enhance rather than inhibit dopaminergic neurotransmission. It is taken by mouth.

References

  1. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 34 (3). 2020. Proposed INN: List 124 – COVID-19 (special edition)
  2. 1 2 3 "SEP 363856". AdisInsight. Springer Nature Switzerland AG. Retrieved 29 December 2018.
  3. 1 2 Brooks M. "New Psychotropic Drug for Schizophrenia Promising in Early Testing". Medscape. Reuters Health Information. Retrieved 29 December 2018.
  4. ↑ "US Sumitomo Pharma Subsidiaries Combine to Form Sumitomo Pharma America". American Pharmaceutical Review. 7 April 2023. Archived from the original on 11 July 2023. Retrieved 10 July 2023.
  5. ↑ "Sunovion Presents Data From Marketed and Late-Stage Development Psychiatric Compounds At The American Psychiatric Association (APA) Annual Meeting 2021". www.businesswire.com. 2021-05-03. Retrieved 2021-09-09.
  6. ↑ "Ulotaront - Otsuka Pharmaceutical/Sumitomo Pharma - AdisInsight".
  7. 1 2 Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, Loebel A (April 2020). "A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia". The New England Journal of Medicine. 382 (16): 1497–1506. doi: 10.1056/NEJMoa1911772 . PMID   32294346.
  8. ↑ "Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia". www.businesswire.com. 2019-05-10. Retrieved 2021-09-09.
  9. 1 2 Brooks M. "'Game Changer' for Schizophrenia on the Horizon?". Medscape. WebMD LLC. Retrieved 21 June 2019.
  10. 1 2 3 "Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia". Bloomberg.com. Bloomberg L.P. 10 May 2019. Retrieved 21 June 2019.
  11. ↑ Koblan K, Hopkins S, Justine K, Hailong C, Goldman R, Loebel A (2019). "O12.5. Efficacy and Safety of Sep-363856, A Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia: A 4-Week, Randomized, Placebo-Controlled Trial". Schizophrenia Bulletin. 45 (Suppl 2): S199. doi: 10.1093/schbul/sbz021.269 . PMC   6455810 .
  12. 1 2 3 4 5 Dedic N, Jones PG, Hopkins SC, Lew R, Shao L, Campbell JE, Spear KL, Large TH, Campbell UC, Hanania T, Leahy E, Koblan KS (October 2019). "SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action" (PDF). J Pharmacol Exp Ther. 371 (1): 1–14. doi:10.1124/jpet.119.260281. PMID   31371483.
  13. 1 2 3 4 Kuvarzin SR, Sukhanov I, Onokhin K, Zakharov K, Gainetdinov RR (July 2023). "Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders". Biomedicines. 11 (7): 1977. doi: 10.3390/biomedicines11071977 . PMC   10377193 . PMID   37509616.
  14. 1 2 Begni V, Sanson A, Luoni A, Sensini F, Grayson B, Munni S, Neill JC, Riva MA (April 2021). "Towards Novel Treatments for Schizophrenia: Molecular and Behavioural Signatures of the Psychotropic Agent SEP-363856". Int J Mol Sci. 22 (8): 4119. doi: 10.3390/ijms22084119 . PMC   8073823 . PMID   33923479.
  15. ↑ "Sunovion – Our Therapies". www.sunovion.us. Sumitomo Dainippon Pharma Co., Ltd. Retrieved 29 December 2018.
  16. ↑ "About Us". www.psychogenics.com. PsychoGenics. Retrieved 29 December 2018.
  17. 1 2 "Drug Receives FDA's Breakthrough Therapy Designation for Treating Individuals with Schizophrenia". Pharmacy Times. Pharmacy & Healthcare Communications, LLC. Retrieved 21 June 2019.
  18. ↑ Tatsumi K, Kirkpatrick B, Strauss GP, Opler M (April 2020). "The brief negative symptom scale in translation: A review of psychometric properties and beyond". European Neuropsychopharmacology. 33: 36–44. doi:10.1016/j.euroneuro.2020.01.018. PMID   32081498. S2CID   211141678.
  19. ↑ Ernst D (2023-08-01). "Disappointing Results for Ulotaront in Two Phase 3 Schizophrenia Trials". Medical Professionals Reference. Retrieved 2023-08-11.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.