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

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

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	Inhibitor 8,504	96.0 nM [IC50]
Norepinephrine transporter 197	Inhibitor 8,504	23.0 nM [IC50]
Serotonin transporter 183	Inhibitor 8,504	12.0 nM [IC50]
Cytochrome P450 2B6 19	Inhibitor 8,504	1.8 µM [IC50]
Norepinephrine transporter 197	Inhibitor 8,504	20.0 nM [IC50]
Serotonin transporter 183	Inhibitor 8,504	14.0 nM [IC50]
Dopamine transporter 183	Inhibitor 8,504	78.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Major depressive disorder 179	Primary	Phase III 665	Unknown
Obesity 206	Primary	Phase I 438	Unknown
Major depressive disorder 179	Primary	Phase II 1,147	Unknown

C_max

Value	Dose	Analyte	Population
37.4 ng/mL	5 mg single, oral	DOV-216303 plasma	Homo sapiens
712 ng/mL	100 mg single, oral	DOV-216303 plasma	Homo sapiens
191 ng/mL	25 mg single, oral	DOV-216303 plasma	Homo sapiens
214 ng/mL	25 mg 3 times / day multiple, oral	DOV-216303 plasma	Homo sapiens
1220 ng/mL	150 mg single, oral	DOV-216303 plasma	Homo sapiens
493 ng/mL	50 mg 2 times / day multiple, oral	DOV-216303 plasma	Homo sapiens
162 ng/mL	25 mg 2 times / day multiple, oral	DOV-216303 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
154 ng × h/mL	5 mg single, oral	DOV-216303 plasma	Homo sapiens
3300 ng × h/mL	100 mg single, oral	DOV-216303 plasma	Homo sapiens
911 ng × h/mL	25 mg single, oral	DOV-216303 plasma	Homo sapiens
2200 ng × h/mL	25 mg 3 times / day multiple, oral	DOV-216303 plasma	Homo sapiens
5520 ng × h/mL	150 mg single, oral	DOV-216303 plasma	Homo sapiens
2460 ng × h/mL	50 mg 2 times / day multiple, oral	DOV-216303 plasma	Homo sapiens
902 ng × h/mL	25 mg 2 times / day multiple, oral	DOV-216303 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
3.4 h	5 mg single, oral	DOV-216303 plasma	Homo sapiens
4 h	100 mg single, oral	DOV-216303 plasma	Homo sapiens
3.6 h	25 mg single, oral	DOV-216303 plasma	Homo sapiens
4.4 h	150 mg single, oral	DOV-216303 plasma	Homo sapiens

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2,057 CYP2B6 926 CYP1A2 2,153	CYPs 33 P-gp 2,052

Drug as perpetrator

Show entries

Target	Modality	Activity
CYP2C9 2,497	inhibitor 4,027	moderate [IC50 99 uM]
CYP2D6 2,546	inhibitor 4,027	yes [IC50 0.78 uM]
CYP1A2 2,333	inhibitor 4,027	yes [IC50 0.8 uM]
CYP3A4 2,633	inhibitor 4,027	yes [IC50 1.3 uM]
CYP2C19 2,141	inhibitor 4,027	yes [IC50 1.6 uM]

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 2,052	substrate 4,014	no
CYPs 33	substrate 4,014	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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PubMed

Show entries

Title	Date	PubMed
DOV 216,303, a "triple" reuptake inhibitor: safety, tolerability, and pharmacokinetic profile.	2004 Dec	15545306
The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties.	2010 Dec	20864506
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

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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).

Show entries

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

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Code System

Code

Type

Description

CAS

410074-73-6

PRIMARY

INN

9554

PRIMARY

EPA CompTox

DTXSID001025835

PRIMARY

WIKIPEDIA

Amitifadine

PRIMARY

ChEMBL

CHEMBL592374

PRIMARY

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ACTIVE MOIETY


					GE0J375F8F

AMITIFADINE

SALT/SOLVATE (PARENT)


					R01R720TVG

AMITIFADINE HYDROCHLORIDE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator