Small Molecule · TS-161
TS-161
TS-161 (active ingredient TP0473292) is an orally bioavailable prodrug of TP0178894, a novel orthosteric metabotropic glutamate mGlu2/3 (GRM2/GRM3) receptor antagonist developed by Taisho Pharmaceutical for major depressive disorder / treatment-resistant depression. The prodrug is rapidly and extensively converted to the active moiety TP0178894, which penetrates the CSF; in rodents it produced acute and prolonged antidepressant-like effects without ketamine-like dissociative side effects.
Also known as: TS-161, TP0473292, TP-0473292, TP0178894, 2144425-75-0
- Modality
- Small molecule
- Chemical class
- bicyclo[3.1.0]hexane amino acid, constrained glutamate analog, ester prodrug
- Chemistry
- Single enantiomer · Prodrug
- Mechanism
- mGlu2 antagonist
- Highest phase
- Discontinued
- Lead indication
- Treatment-resistant depression
- Developer
- Taisho Pharmaceutical Co., Ltd.
- Trials
- 2 tracked · 1 sites
- Next catalyst
- 2025-06-10 — Full results (Treatment-resistant depression)
Mechanism of action
TS-161 (TP0473292) is an inactive oral prodrug that is rapidly converted in vivo to TP0178894, a novel orthosteric antagonist of the metabotropic glutamate type 2 and type 3 (mGlu2/mGlu3; GRM2/GRM3) receptors. Antagonism of presynaptic mGlu2/3 autoreceptors is thought to enhance glutamatergic transmission, producing rapid antidepressant-like effects mechanistically related to ketamine but without ketamine-like dissociative effects in preclinical models.
| Target | Action | Affinity |
|---|---|---|
| mGlu2primaryGRM2 | Antagonist | Ki 4.27 nMⓘ |
| mGlu3GRM3 | Antagonist | Ki 2.83 nMⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| TS-161 oral capsuleester prodrug (double-ester promoiety converted to active metabolite TP0178894) Oral capsules; Phase 1 single doses 15-400 mg and multiple once-daily doses 50-150 mg for 10 days; Phase 2 TRD study (NCT04821271) uses the oral form | Oral | Once daily | t½ 13 h · Tmax 4 h |
Development timeline
- Upcoming
- Phase 2 trial NCT04821271 terminated due to low recruitment (11 actual enrollment); primary completion 2024-05-23. Results posted 2025-06-10 showed no separation from placebo on MADRS at day 21 (p=0.91, zero remitters) - a negative efficacy readout.
- Phase 2 proof-of-concept crossover study in treatment-resistant depression (NCT04821271, lead sponsor NIMH, collaborator Taisho) started June 10, 2021.
- First-in-human Phase 1 single/multiple ascending dose study in healthy participants (NCT03919409, sponsor Taisho Pharmaceutical R&D Inc., 70 participants) completed; primary completion Feb 11, 2020. Prodrug well tolerated; extensive conversion to active moiety TP0178894 with CSF penetration.
TS-161 for Treatment-resistant depression
DiscontinuedDiscontinuedTreatment-resistant depression indication →
Phase 2 proof-of-concept program of TS-161 in treatment-resistant depression (NIMH-led, Taisho collaborator; NCT04821271) was terminated due to low recruitment (11 participants) and, on the posted results, FAILED its primary endpoint: change in MADRS to day 21 was 28.02 (TS-161) vs 27.79 (placebo), p=0.91, with no remitters. No active development for TRD is evident. Program marked discontinued.
Readouts
- 2025-06-10AnticipatedFull results
Clinical trials
NCT04821271Phase 2Discontinuedn=11
An Investigation of the Antidepressant Effects of the mGlu2/3 Receptor Antagonist TS-161 in Treatment-Resistant Depression
missedprimaryChange in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to day 21 — MADRS change: TS-161 28.02 (SE 1.9) vs placebo 27.79 (SE 1.62) (0.91)
No statistically significant difference between TS-161 (50-100 mg/day) and placebo on MADRS change to day 21 (p=0.91, t-test of estimated marginal means from a linear mixed model). Zero participants achieved remission in either arm. Trial was also terminated early for low recruitment (n=11), but the primary endpoint was analyzed and showed no antidepressant separation from placebo.
NCT03919409Phase 1Completedn=70
First-in-Human Study With Single and Multiple Doses of TS-161 in Healthy Participants
Identifiers
- PubChem CID 132049989
- FDA UNII 81CY1K7KZU
Sources
- Antidepressant Effects of TS-161 in Treatment-Resistant Depression (NCT04821271) — ClinicalTrials.gov / NIMH
- 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 — International Journal of Neuropsychopharmacology (Oxford) 2022;25(2):106
- First-in-Human Study With Single and Multiple Doses of TS-161 in Healthy Participants (NCT03919409) — ClinicalTrials.gov / Taisho Pharmaceutical R&D Inc.