Esmethadone

Summary

Esmethadone (CHEMBL350719) is a phase-3 clinical-stage small-molecule NMDA receptor antagonist; indicated across 3 conditions including major depressive disorder and neuralgia.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Indications: 3 conditions
• Clinical trials: 29
• Chemistry: 309.4 Da · C21H27NO

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL350719
Name	Esmethadone
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	643985
ChEBI	CHEBI:167308
Molecular formula	C21H27NO
Molecular weight	309.4
InChIKey	USSIQXCVUWKGNF-KRWDZBQOSA-N

SMILES: CCC(=O)C(C[C@H](C)N(C)C)(C1=CC=CC=C1)C2=CC=CC=C2

IUPAC name: (6S)-6-(dimethylamino)-4,4-diphenylheptan-3-one

ChEBI definition: A 6-(dimethylamino)-4,4-diphenylheptan-3-one that has (S)-configuration. It is the less active enantiomer of methadone and has very little activity on opioid receptors and mainly responsible for the inhibition of hERG K+ channels and thus for cardiac toxicity. The drug is currently under clinical development for the treatment of major depressive disorder.

Pharmacological roles (ChEBI): NMDA receptor antagonist, opioid analgesic.

Also known as: (s)-methadone, D-methadone, Dextromethadone, Esmetadona, Esmethadone, Rel-1017, REL-1017, S-methadone, (S)-methadone, ESMETHADONE, METHADONE HYDROCHLORIDE

Parent form; salt/anhydrous children: CHEMBL5095396

Patent coverage: 12,222 distinct patent families (26,004 SureChEMBL compound mentions), from 1 matched compound structure(s). Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Broader ChEMBL bioactivity targets: 7 (assay-derived). Sample: Glutamate NMDA receptor; GRIN1/GRIN2B, Glutamate NMDA receptor; GRIN1/GRIN2A, Glutamate NMDA receptor, Opioid receptor, Mu-type opioid receptor, Ionotropic glutamate receptor NMDA 1/2C, Ionotropic glutamate receptor NMDA 1/2D.

Bioactivity

ChEMBL activities: 5 potent at pChembl ≥ 5 of 8 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P33533	6.96	Ki	110	nM	CHEMBL_ACT_589880
OPRM1	6.35	Ki	446.7	nM	CHEMBL_ACT_29198115
P35439	5.58	Ki	2630	nM	CHEMBL_ACT_29198103
P33533	5.5	Ki	3200	nM	CHEMBL_ACT_589881
GRIN1	5.2	IC50	6310	nM	CHEMBL_ACT_29198044

Target pathways

No target-pathway data for this drug (no mapped target genes).

Indications & clinical

Indications

3 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
major depressive disorder	3	MONDO:0002009	MONDO:0002009
neuralgia	1	MONDO:0021667	EFO:0005762

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 29.

Phase distribution

Phase	Trials
PHASE1	9
PHASE3	8
Not specified	4
PHASE4	3
PHASE2	3
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT02989597	PHASE4	TERMINATED	Intraoperative Methadone Administration for Improved Pain Control in Spinal Fusion Patients
NCT06086171	PHASE4	COMPLETED	Perioperative Methadone Compared to Placebo in Elderly Hip Fracture Patients
NCT05831345	PHASE3	RECRUITING	Intraoperative Methadone for the Prevention of Postoperative Pain
NCT07226076	PHASE3	RECRUITING	Methadone in TKA for Post-op Pain and Opioid Reduction
NCT04680286	PHASE3	TERMINATED	Intraoperative Methadone in Children Undergoing Surgery
NCT04688164	PHASE3	COMPLETED	A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD)
NCT04855747	PHASE3	TERMINATED	A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD)
NCT04855760	PHASE3	COMPLETED	Safety of REL-1017 for Major Depressive Disorder
NCT05081167	PHASE3	COMPLETED	A Study to Assess the Efficacy and Safety of REL-1017 as Monotherapy for Major Depressive Disorder (MDD)
NCT06011577	PHASE3	TERMINATED	Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as Adjunctive Treatment for MDD
NCT00588640	PHASE1/PHASE2	COMPLETED	Study of D-Methadone in Patients With Chronic Pain
NCT01795495	PHASE2	COMPLETED	Methadone vs Magnesium in Spinal Fusion
NCT03051256	PHASE2	COMPLETED	Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD
NCT04145674	PHASE2	SUSPENDED	A Proof of Concept, Phase 2, Double-blind, Randomized Trial With d-Methadone Product Versus Placebo
NCT06877858	PHASE1	RECRUITING	MethaLoad Dose-Finding Study
NCT00000788	PHASE1	COMPLETED	A Study to Assess the Effect of Concomitant Administration of Fluconazole on the Clinical Pharmacokinetics of Methadone
NCT00000800	PHASE1	COMPLETED	Methadone Effects on Zidovudine (ZDV, AZT) Disposition
NCT00000906	PHASE1	COMPLETED	Interactions of HIV Protease Inhibitors and Methadone in HIV-Infected Patients
NCT00930332	PHASE1	TERMINATED	Methadone Hydrochloride as First-Line Therapy in Treating Patients With Chronic Neuropathic Cancer Pain
NCT02531906	PHASE1	COMPLETED	Gabapentin, Methadone Hydrochloride, and Oxycodone Hydrochloride in Improving Quality of Life in Patients With Stage II-IV Head and Neck Cancer During Chemoradiation
NCT03637361	PHASE1	COMPLETED	Safety, Tolerability and Pharmacokinetics of Single Ascending Doses of REL-1017 (d-Methadone)
NCT03638869	PHASE1	COMPLETED	Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of REL-1017 (d-Methadone)
NCT04112550	PHASE1	UNKNOWN	Clinical Effectiveness of Pre-operative Methadone in Single Level Lateral Transpsoas Interbody Fusions
NCT03525509	EARLY_PHASE1	COMPLETED	Epidural Methadone in Healthy Volunteers
NCT00001008	Not specified	COMPLETED	A Study of Azidothymidine Plus Methadone in Patients With AIDS and AIDS Related Complex (ARC)
NCT00726830	Not specified	TERMINATED	Methadone, Morphine, or Oxycodone in Treating Pain in Patients With Cancer
NCT01560442	Not specified	UNKNOWN	Pupillometry and Pain Thresholds Patients Substituted by Methadone and Buprenorphine
NCT06009003	Not specified	TEMPORARILY_NOT_AVAILABLE	Individual Patient Esmethadone (REL-1017) Expanded Access Program

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 11 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

No competitor molecules sharing a primary target (ChEMBL phase ≥2 or PubChem drug-class).