AMITIFADINE

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

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

Amitifadine is a novel, serotonin-preferring triple reuptake inhibitor with a relative potency to inhibit serotonin (5-HT), norepinephrine (NE), and dopamine (DA) reuptake. Amitifadine is most potent against the 5-HT transporter. Amitifadine did not cause marked inhibition of major CYP450 isoenzymes, and had a good safety margin at the hERG ion channel. Initial clinical trial in patients with severe major depression demonstrated significant antidepressant activity with amitifadine, including attenuating symptoms of anhedonia, and a tolerability profile that was comparable to placebo. Amitifadine did not increase any sexual side effects as well as weight gain. It’s in phase III clinical trial for the treatment of Major depressive disorder.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Dopamine transporter 180 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12586204	Inhibitor 8297	96.0 nM [IC50]
Norepinephrine transporter 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12586204	Inhibitor 8297	23.0 nM [IC50]
Serotonin transporter 178 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12586204	Inhibitor 8297	12.0 nM [IC50]
Cytochrome P450 2B6 19 Target ID: CHEMBL4729 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23826879	Inhibitor 8297	1.8 µM [IC50]
Norepinephrine transporter 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Inhibitor 8297	20.0 nM [IC50]
Serotonin transporter 178 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Inhibitor 8297	14.0 nM [IC50]
Dopamine transporter 180 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Inhibitor 8297	78.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Major depressive disorder 173 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 656	Unknown Approved Use Unknown
Obesity 203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18089843 http://adisinsight.springer.com/trials/700011693	Primary	Phase I 428	Unknown Approved Use Unknown
Major depressive disorder 173 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16958986	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
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
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
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
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
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
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
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

AUC

Value	Dose	Analyte	Population
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
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
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
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
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
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
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

T_1/2

Value	Dose	Analyte	Population
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
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
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
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

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478 CYP2B6 810 CYP1A2 1524	MAO-A 5 CYPs 33 P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	moderate [IC50 99 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 0.78 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 0.8 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 1.3 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/ \| https://pubmed.ncbi.nlm.nih.gov/24974340/	yes [IC50 1.6 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/	yes [IC50 1.8 uM]

Drug as victim

Target	Modality	Activity
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363681341	no
CYPs 33	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/	yes
MAO-A 5	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23826879/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/18954985/

PubMed

Title	Date	PubMed
Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor.	2003 Feb 14	12586204
"Broad spectrum" antidepressants: is more better for the treatment of depression?	2003 Nov 7	14561522
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 Mar	18089843
Synthesis and pharmacological characterization of bicyclic triple reuptake inhibitor 3-aryl octahydrocyclopenta[c]pyrrole analogues.	2011 Aug 11	21739935
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 Jan	21925682
Biopharmaceutical characterization, metabolism, and brain penetration of the triple reuptake inhibitor amitifadine.	2013 Mar	23826879
Investigational drugs for treating major depressive disorder.	2017 Jan	27960559

Patents

Sample Use Guides

In Vivo Use Guide

100 mg DOV 216,303 (50 mg b.i.d.)

Route of Administration: Oral

In Vitro Use Guide

DOV 216,303 inhibits [(3)H]NE, [(3)H]5-HT, and [(3)H]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC(50) values of approximately 20, 14, and 78 nM, respectively. DOV 216,303 is active in tests predictive of antidepressant activity including the mouse forced swim test and reversal of tetrabenazine-induced ptosis and locomotor depression.

Name

Type

Language

AMITIFADINE

Official 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

amitifadine [INN]

Common Name

English

Code System Code Type Description

CAS

410074-73-6