AMITIFADINE

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C11H11Cl2N
Molecular Weight	228.118
Optical Activity	( + )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

ClC1=C(Cl)C=C(C=C1)[C@@]23C[C@@H]2CNC3

InChI

InChIKey=BSMNRYCSBFHEMQ-KCJUWKMLSA-N

InChI=1S/C11H11Cl2N/c12-9-2-1-7(3-10(9)13)11-4-8(11)5-14-6-11/h1-3,8,14H,4-6H2/t8-,11+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C11H11Cl2N
Molecular Weight	228.118
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27960559https://www.ncbi.nlm.nih.gov/pubmed/16958986
Curator's Comment: description was created based on several sources, including http://www.siliconinvestor.com/readmsg.aspx?msgid=21695155

DOV 216,303 [(+/-)-1-(3, 4-dichlorophenyl)-3-azabicyclo-[3.1.0] hexane hydrochloride] is the prototype of a class of compounds referred to as "triple" reuptake inhibitors. DOV 216,303 were licensed from Wyeth in 1998. This compound inhibits the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. In August 2004, DOV entered into a development and commercialization partnership for the triple reuptake inhibitors (DOV 21,947 and DOV 216,303) with Merck for depression.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Dopamine transporter 183 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12586204	Inhibitor 8504	96.0 nM [IC50]
Norepinephrine transporter 197 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12586204	Inhibitor 8504	23.0 nM [IC50]
Serotonin transporter 183 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12586204	Inhibitor 8504	12.0 nM [IC50]
Cytochrome P450 2B6 19 Target ID: CHEMBL4729 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23826879	Inhibitor 8504	1.8 µM [IC50]
Norepinephrine transporter 197 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Inhibitor 8504	20.0 nM [IC50]
Serotonin transporter 183 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Inhibitor 8504	14.0 nM [IC50]
Dopamine transporter 183 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Inhibitor 8504	78.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Major depressive disorder 179 Sources: https://clinicaltrials.gov/ct2/show/NCT00659347 https://www.ncbi.nlm.nih.gov/pubmed/21925682 https://www.ncbi.nlm.nih.gov/pubmed/27960559	Primary	Phase III 665	Unknown Approved Use Unknown
Obesity 206 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18089843 http://adisinsight.springer.com/trials/700011693	Primary	Phase I 438	Unknown Approved Use Unknown
Major depressive disorder 179 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Primary	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
37.4 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
712 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
191 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
214 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	25 mg 3 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1220 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
493 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	50 mg 2 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
162 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	25 mg 2 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
154 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
3300 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
911 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
2200 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	25 mg 3 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
5520 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
2460 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	50 mg 2 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
902 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	25 mg 2 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
3.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
3.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
4.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15545306/	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:	DOV-216303 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2057 CYP2B6 926 CYP1A2 2153	CYPs 33 P-gp 2052

Drug as perpetrator

Target	Modality	Activity
CYP2C9 2497	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	moderate [IC50 99 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 0.78 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 0.8 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 1.3 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 1.6 uM]
CYP2B6 1160	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/	yes [IC50 1.8 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 2052	substrate 4014 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363681341	no
CYPs 33	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/18954985/

PubMed

Title	Date	PubMed
Investigational drugs for treating major depressive disorder.	2017-01	27960559
Biopharmaceutical characterization, metabolism, and brain penetration of the triple reuptake inhibitor amitifadine.	2013-03	23826879
Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial.	2012-01	21925682
Synthesis and pharmacological characterization of bicyclic triple reuptake inhibitor 3-aryl octahydrocyclopenta[c]pyrrole analogues.	2011-08-11	21739935
Further structure-activity relationship studies on 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: identification of compounds with triple uptake inhibitory activity as potential antidepressant agents.	2011-04-28	21446715
The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties.	2010-12	20864506
The putative antidepressant DOV 216,303, a triple reuptake inhibitor, increases monoamine release in the prefrontal cortex of olfactory bulbectomized rats.	2010-05-10	20153745
The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects.	2008-12	18789657
The triple uptake inhibitor (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane hydrochloride (DOV 21947) reduces body weight and plasma triglycerides in rodent models of diet-induced obesity.	2008-03	18089843
Triple reuptake inhibitors ("broad spectrum" antidepressants).	2007-04	17430151
Preclinical and clinical pharmacology of DOV 216,303, a "triple" reuptake inhibitor.	2006	16958986
DOV 216,303, a "triple" reuptake inhibitor: safety, tolerability, and pharmacokinetic profile.	2004-12	15545306
"Broad spectrum" antidepressants: is more better for the treatment of depression?	2003-11-07	14561522
Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor.	2003-02-14	12586204

Patents

Sample Use Guides

In Vivo Use Guide

25 mg or 50 mg twice a day

Route of Administration: Oral

In Vitro Use Guide

Amitifadine was a moderate inhibitor of the human isoforms of the major drug metabolizing enzymes CYP2D6, CYP3A4, CYP2C9, and CYP2C19 (IC50 = 9 - 100 uM).

Substance Class	Chemical Created by `admin` on `Mon Mar 31 20:54:54 GMT 2025` Edited by `admin` on `Mon Mar 31 20:54:54 GMT 2025`
Record UNII	GE0J375F8F
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AMITIFADINE

Official Name

English

amitifadine [INN]

Preferred Name

English

3-AZABICYCLO(3.1.0)HEXANE, 1-(3,4-DICHLOROPHENYL)-, (1R,5S)-

Systematic Name

English

(1R,5S)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane

Systematic Name

English

EB-1010

Code

English

Amitifadine [WHO-DD]

Common Name

English

AMITIFADINE [USAN]

Common Name

English

DOV-21,947

Code

English

DOV-21947

Code

English

EB1010

Code

English

Code System Code Type Description

CAS

410074-73-6