Background:
Major depressive disorder (MDD) is a common, chronic mental illness. It can take weeks to months for antidepressants to work. Researchers want to test a new drug that might act more rapidly.
Objective:
To see if TS-161 will improve symptoms of depression in people with MDD.
Eligibility:
Adults ages 18-65 with MDD without psychotic features.
Design:
Participants will be screened under a separate protocol. They will have blood tests. They will complete surveys about their symptoms.
Participants will have an inpatient visit at NIH. Participation may last 12-16 weeks.
During the first phase of the study, participants will be tapered off their psychiatric medicines. For 2 weeks they will have a drug-free period.
During Phase II participants will take TS-161 or placebo. They will take TS-161 for 3 weeks and placebo for 3 weeks. In between the 3-week time period, they will have 2-3 weeks where they will be drug free. Participants will also have the following tests during this time:
* Interviews
* Physical exams
* Psychological tests and surveys about their symptoms
* Blood draws and urine samples
* They may complete tests of mood and thinking
* MRI (Magnetic resonance imaging): Participants will lie in a machine that takes pictures of their brain.
* Functional MRIs: They will perform tasks displayed on a computer screen inside the MRI scanner
* MEG (magnetoencephalography): Participants will lie down and do tasks of memory, attention, and thinking. A cone lowered on their head will record brain activity.
* Electrocardiograms to record the heart s electrical activity. Electrodes will be placed on the skin....

开始日期2021-06-10

申办/合作机构

National Institute of Mental Health

[+1]

NCT03919409 / Completed临床1期

A Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TS-161 Administered Orally to Healthy Male and Female Participants

This is a Phase 1, first-in-human study involving single and multiple oral doses of TS-161 in healthy male and female participants. The safety, tolerability, pharmacokinetics and pharmacodynamics of TS-161 will be evaluated.
The study includes 3 parts; Part A (single ascending dose: Cohorts 1 to 5) , Part B (single dose, cerebrospinal fluid [CSF] collection: Cohort 6), and Part C (multiple ascending dose: Cohorts 7 to 9). Participants will be assigned to one of the 9 Cohorts.

开始日期2019-06-03

申办/合作机构

Taisho Pharmaceutical R&D, Inc.

100 项与 TS-161 相关的临床结果

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100 项与 TS-161 相关的转化医学

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100 项与 TS-161 相关的专利（医药）

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项与 TS-161 相关的文献（医药）

2023-10-01·European Archives of Psychiatry and Clinical Neuroscience

mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development

Review

作者: Watanabe, Mai ; Chaki, Shigeyuki

Triggered by the ground-breaking finding that ketamine exerts robust and rapid-acting antidepressant effects in patients with treatment-resistant depression, glutamatergic systems have attracted attention as targets for the development of novel antidepressants. Among glutamatergic systems, group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, are of interest because of their modulatory roles in glutamatergic transmission. Accumulating evidence has indicated that mGlu2/3 receptor antagonists have antidepressant-like effects in rodent models that mirror those of ketamine and that mGlu2/3 receptor antagonists also share underlying mechanisms with ketamine that are responsible for these antidepressant-like actions. Importantly, contrary to their antidepressant-like profile, preclinical studies have revealed that mGlu2/3 receptor antagonists are devoid of ketamine-like adverse effects, such as psychotomimetic-like behavior, abuse potential and neurotoxicity. Despite some discouraging results for an mGlu2/3 receptor antagonist decoglurant (classified as a negative allosteric modulator [NAM]) in patients with major depressive disorder, clinical trials of two mGlu2/3 receptor antagonists, a phase 2 trial of TS-161 (an orthosteric antagonist) and a phase 1 trial of DSP-3456 (a NAM), are presently on-going. mGlu2/3 receptors still hold promise for the development of safer and more efficacious antidepressants.

2022-09-01·Pharmacology Biochemistry and Behavior

Clinical investigations of compounds targeting metabotropic glutamate receptors

Review

作者: Smith, Jodi L ; Witkin, Jeffrey M ; Pandey, Kamal P

Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.

2022-02-11·International Journal of Neuropsychopharmacology2区 · 医学

Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents

2区 · 医学

ArticleOA

作者: Zarate, Carlos A ; Kinoshita, Kohnosuke ; Chaki, Shigeyuki ; Iijima, Michihiko ; Watanabe, Mai ; Marcy, Brian ; Watase, Hirotaka ; Marumo, Toshiyuki ; Hiroki, Ayano

AbstractBackgroundTP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects.MethodsThis was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15–400 mg TS-161) and 10-day multiple-ascending dose (50–150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161.ResultsFollowing single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness.ConclusionsThe mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.

100 项与 TS-161 相关的药物交易

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