NEFAZODONE

First approved in 1994

Details

Stereochemistry	ACHIRAL
Molecular Formula	C25H32ClN5O2
Molecular Weight	470.007
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC1=NN(CCCN2CCN(CC2)C3=CC(Cl)=CC=C3)C(=O)N1CCOC4=CC=CC=C4

InChI

InChIKey=VRBKIVRKKCLPHA-UHFFFAOYSA-N

InChI=1S/C25H32ClN5O2/c1-2-24-27-31(25(32)30(24)18-19-33-23-10-4-3-5-11-23)13-7-12-28-14-16-29(17-15-28)22-9-6-8-21(26)20-22/h3-6,8-11,20H,2,7,12-19H2,1H3

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB01149
Curator's Comment: Description was created based on several sources, including https://www.drugs.com/pro/nefazodone.html

Nefazodone hydrochloride (trade name Serzone) is an antidepressant drug marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries, due to the small possibility of hepatic (liver) injury, which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in 250,000 to 300,000 patient-years. On May 20, 2004, Bristol-Myers Squibb discontinued the sale of Serzone in the United States. Within the serotonergic system, nefazodone acts as an antagonist at type 2 serotonin (5-HT2) post-synaptic receptors and, like fluoxetine-type antidepressants, inhibits pre-synaptic serotonin (5-HT) reuptake. These mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally. Nefazodone also antagonizes alpha(1)-adrenergic receptors, producing sedation, muscle relaxation, and a variety of cardiovascular effects. Nefazodone's affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, and beta or alpha(2)-adrenergic receptors is not significant.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serotonin 2a (5-HT2a) receptor 231 Target ID: CHEMBL224 Sources: http://www.drugbank.ca/drugs/DB01149	Antagonist 2778	5.8 nM [Ki]
Serotonin transporter 178 Target ID: CHEMBL228 Sources: http://www.drugbank.ca/drugs/DB01149	Antagonist 2778	290.0 nM [Ki]
Adrenergic receptor alpha-1 169 Target ID: CHEMBL2094251 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9400006	Antagonist 2778	5.5 nM [Ki]
Adrenergic receptor alpha-2 113 Target ID: CHEMBL2095158 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9400006	Antagonist 2778	84.0 nM [Ki]
Serotonin 1a (5-HT1a) receptor 172 Target ID: CHEMBL214 Sources: http://www.drugbank.ca/drugs/DB01149	Antagonist 2778	52.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Depression 235 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/076037s011lbl.pdf	Primary		Approved 8429	NEFAZODONE HYDROCHLORIDE Approved Use Nefazodone hydrochloride tablets are indicated for the treatment of depression. When deciding among the alternative treatments available for this condition, the prescriber should consider the risk of hepatic failure associated with Nefazodone hydrochloride treatment. In many cases, this would lead to the conclusion that other drugs should be tried first. Launch Date 1.06358401E12

C_max

Value	Dose	Analyte	Population
1588 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
880 μg/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
415 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
276 μg/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
6378 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
3213 μg × h/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1220 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
787 μg × h/L REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
7 h REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8951188/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
5.7 h REVIEW https://link.springer.com/article/10.2165/00003088-199733040-00002	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	NEFAZODONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	unhealthy, adult n = 12 Health Status: unhealthy Condition: hepatic cirrhosis Age Group: adult Sex: unknown Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	unhealthy, adult n = 12 Health Status: unhealthy Condition: renal impairment Age Group: adult Sex: unknown Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/
430 mg 1 times / day steady, oral (mean) Highest studied dose Dose: 430 mg, 1 times / day Route: oral Route: steady Dose: 430 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10817106/	unhealthy, adult n = 19 Health Status: unhealthy Condition: Posttraumatic stress disorder Age Group: adult Sex: M Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/10817106/	Other AEs: Headaches, Dry mouth... Other AEs: Headaches (53%) Dry mouth (42%) Diarrhea (42%) Sources: https://pubmed.ncbi.nlm.nih.gov/10817106/
600 mg 1 times / day steady, oral (max) Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 1	unhealthy, adult n = 394 Health Status: unhealthy Condition: major depression Age Group: adult Sex: unknown Population Size: 394 Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 1	Other AEs: Dry mouth, Nausea... Other AEs: Dry mouth (25%) Nausea (22%) Dizziness (17%) Constipation (14%) Asthenia (11%) Light headedness (10%) Blurred vision (9%) Confusion (7%) Abnormal vision (7%) Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 1
600 mg 1 times / day steady, oral (max) Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 2	unhealthy, adult n = 394 Health Status: unhealthy Condition: major depression Age Group: adult Sex: unknown Population Size: 394 Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 2	Other AEs: Somnolence... Other AEs: Somnolence (25%) Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 2
600 mg 1 times / day steady, oral (max) Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 1	unhealthy, adult n = 565 Health Status: unhealthy Condition: major depression Age Group: adult Sex: unknown Population Size: 565 Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 1	Disc. AE: Nausea, Headache... AEs leading to discontinuation/dose reduction: Nausea (3.5%) Headache (2.9%) Dizziness (1.9%) Somnolence (1.5%) Insomnia (1.5%) Asthenia (1.3%) Agitation (1.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/8876863/ Page: Table 1
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	healthy, elderly n = 12 Health Status: healthy Age Group: elderly Sex: unknown Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	healthy, younger n = 12 Health Status: healthy Age Group: younger Sex: unknown Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/	Other AEs: Nausea and vomiting... Other AEs: Nausea and vomiting Sources: https://pubmed.ncbi.nlm.nih.gov/8665999/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 substrate 1737		inhibitor 1852 substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 P-gp 1461 BSEP 402	P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	weak
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/11452702/	yes [IC50 4.7 uM]
BSEP 403	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16410371/	yes [IC50 9 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	yes

Drug as victim

Target	Modality	Activity	Metabolite
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11452702/	no
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	yes	mCPP 2
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9342502/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/24374264/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:7495	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:7495
ChemicalBook	CB8144863	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8144863
MolPort	MolPort-003-983-466	https://www.molport.com/shop/molecule-link/MolPort-003-983-466
eMolecules	592758	https://www.emolecules.com/cgi-bin/more?vid=592758

PubMed

Title	Date	PubMed
Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: cytochromes mediating transformation, and P450-3A4 inhibitory actions.	1999 Jul	10445380
Depression, sleep physiology, and antidepressant drugs.	2001	11568979
Separation anxiety disorder in children and adolescents: epidemiology, diagnosis and management.	2001	11460893
Algorithm for the treatment of chronic depression.	2001	11310816
Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction.	2001	11229449
Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials.	2001 Apr	11379839
[Serotonin-noradrenaline reuptake inhibitors(SNRIs)].	2001 Aug	11519152
Opposite effects of nefazodone in two human models of anxiety.	2001 Aug	11498723
Comparison between two models of experimental anxiety in healthy volunteers and panic disorder patients.	2001 Dec	11801299
Screening for detection of new antidepressants, neuroleptics, hypnotics, and their metabolites in urine by GC-MS developed using rat liver microsomes.	2001 Feb	11206046
Current trends in the development of new antidepressants.	2001 Feb	11172668
The 'dalhousie serotonin cocktail' for treatment-resistant major depressive disorder.	2001 Jun	11448087
Depression and anxiety disorders.	2001 Jun	11430175
Antidepressants and ejaculation: a double-blind, randomized, placebo-controlled, fixed-dose study with paroxetine, sertraline, and nefazodone.	2001 Jun	11386492
Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy.	2001 Mar	11465683
Intermittent, luteal phase nefazodone treatment of premenstrual dysphoric disorder.	2001 Mar	11277610
Increase in plasma levels of clozapine and norclozapine after administration of nefazodone.	2001 May	11411823
Nefazodone for chronic daily headache prophylaxis: an open-label study.	2001 May	11380644
Identification and treatment of depression in a cohort of patients maintained on chronic peritoneal dialysis.	2001 May	11325684
Possible interaction of zopiclone and nefazodone.	2001 Nov	11724087
Pharmacotherapy for post-traumatic stress disorder: a comprehensive review.	2001 Oct	11825301
An open-label, 12-week clinical and sleep EEG study of nefazodone in chronic combat-related posttraumatic stress disorder.	2001 Oct	11816868
Antidepressants in social anxiety disorder.	2001 Sep	11588653
Clinically significant drug interactions with antidepressants in the elderly.	2002	12038880
Overview of psychiatric disorders and the role of newer antidepressants.	2002	11890562
Increased premenstrual dosing of nefazodone relieves premenstrual magnification of depression.	2002	11816054
Prevalence of sexual dysfunction among newer antidepressants.	2002 Apr	12000211
Serzone. Beware of dangerous liver problems.	2002 Apr	11969010
Human CYP3A4 and the metabolism of nefazodone and hydroxynefazodone by human liver microsomes and heterologously expressed enzymes.	2002 Apr	11872324
Nefazodone and liver damage.	2002 Aug	12217828
An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding.	2002 Dec 30	12477599
Does psychosocial functioning improve independent of depressive symptoms? A comparison of nefazodone, psychotherapy, and their combination.	2002 Jan 15	11822991
Differential effects of nefazodone and cognitive behavioral analysis system of psychotherapy on insomnia associated with chronic forms of major depression.	2002 Jun	12088160
Nefazodone treatment of dysthymic disorder an open, long-term, prospective pilot study.	2002 May	12188098
Pharmacological interactions of statins.	2002 May	12044584
Symptomatic and syndromal anxiety in chronic forms of major depression: effect of nefazodone, cognitive behavioral analysis system of psychotherapy, and their combination.	2002 May	12025827
Effects of smoked marijuana in healthy and HIV + marijuana smokers.	2002 Nov	12412834
Reversible penile priapism associated with nefazodone.	2002 Sep	12383175

Patents

Sample Use Guides

In Vivo Use Guide

Initial dose: 200 mg orally per day in two divided doses Maintenance dose: 300 to 600 mg orally per day

Route of Administration: Oral

In Vitro Use Guide

In vitro biliary excretion of micafungin in humans and rats was reduced by 75% in the presence of the bile salt export pump (BSEP) inhibitor nefazodone (25 uM)

Name

Type

Language

NEFAZODONE

Official Name

English

nefazodone [INN]

Common Name

English

1-(3-(4-(M-CHLOROPHENYL)-1-PIPERAZINYL)PROPYL)-3-ETHYL-4-(2-PHENOXYETHYL)-.DELTA.(SUP 2)-1,2,4-TRIAZOLIN-5-ONE

Common Name

English

NEFAZODONE [VANDF]

Common Name

English

3H-1,2,4-TRIAZOL-3-ONE, 2-(3-(4-(3-CHLOROPHENYL)-1-PIPERAZINYL))PROPYL)-5-ETHYL-2,4-DIHYDRO-4-(2-PHENOXYETHYL)-

Common Name

English

NEFAZODONE [MI]

Common Name

English

Nefazodone [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C265