Nefazodone

Summary

Nefazodone (CHEMBL623) is an approved small-molecule antidepressant (ATC N06AX06) targeting CYP3A4, HTR2A, and SLC6A2; indicated across 3 conditions including depressive disorder and cocaine dependence.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N06AX06
• Targets: 4 (CYP3A4, HTR2A, SLC6A2…)
• Indications: 3 conditions
• Clinical trials: 5
• Chemistry: 470 Da · C25H32ClN5O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL623
Name	Nefazodone
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	4449
ChEBI	CHEBI:7494
ATC	N06AX06
Molecular formula	C25H32ClN5O2
Molecular weight	470
InChIKey	VRBKIVRKKCLPHA-UHFFFAOYSA-N

SMILES: CCC1=NN(C(=O)N1CCOC2=CC=CC=C2)CCCN3CCN(CC3)C4=CC(=CC=C4)Cl

IUPAC name: 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazol-3-one

Pharmacological roles (ChEBI): antidepressant, serotonergic antagonist, serotonin uptake inhibitor, α-adrenergic antagonist, analgesic.

Also known as: Nefazodona, Nefazodone, SID49666410, SID50111710, nefazodone, NEFAZODONE, SID29217604, Nefazadone

Parent form; salt/anhydrous children: CHEMBL1200492

Patent coverage: 5,409 distinct patent families (21,375 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 21,194 (99%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
CYP3A4	CYP3A4	Inhibition	6	0%	P08684
HTR2A	5-HT2A receptor	Antagonist	8.24	0%	P28223
SLC6A2	NET	Inhibition	6.44	0.4%	P23975
SLC6A4	SERT	Inhibition	6.7	0.7%	P31645

Broader ChEMBL bioactivity targets: 39 (assay-derived). Sample: ATP-binding cassette sub-family C member 4, 5-hydroxytryptamine receptor 2B, Alpha-2A adrenergic receptor, Cholecystokinin receptor type A, Alpha-2C adrenergic receptor, Histamine H2 receptor, Alpha-2B adrenergic receptor, Equilibrative nucleoside transporter 1, D(1A) dopamine receptor, Thromboxane A2 receptor.

Bioactivity

ChEMBL activities: 55 potent at pChembl ≥ 5 of 62 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
HTR2A	8.24	Ki	5.8	nM	CHEMBL_ACT_6339205
P14842	8.15	Ki	7	nM	CHEMBL_ACT_19101893
P14842	8.15	Ki	7.1	nM	CHEMBL_ACT_29098210
CYP3A4	7.82	IC50	15	nM	CHEMBL_ACT_12163651
HTR2A	7.72	AC50	19.1	nM	CHEMBL_ACT_25173590
P19327	7.28	Ki	52	nM	CHEMBL_ACT_19101894
HTR2B	7.08	AC50	84	nM	CHEMBL_ACT_25164089
HTR2C	6.89	AC50	130	nM	CHEMBL_ACT_25131734
ADRA1A	6.88	AC50	130.5	nM	CHEMBL_ACT_25138409
P31652	6.86	Ki	137	nM	CHEMBL_ACT_148577
HTR1A	6.8	Kd	158.5	nM	CHEMBL_ACT_2930070
SLC6A4	6.7	Kd	200	nM	CHEMBL_ACT_148573
P31652	6.66	Ki	220	nM	CHEMBL_ACT_29098211
HTR7	6.62	AC50	237.2	nM	CHEMBL_ACT_25119092
HTR1A	6.59	AC50	254.2	nM	CHEMBL_ACT_25164482
DRD4	6.57	AC50	271	nM	CHEMBL_ACT_25127365
DRD2	6.57	AC50	270	nM	CHEMBL_ACT_25140257
SLC6A4	6.54	Ki	290	nM	CHEMBL_ACT_6339204
ADRA2B	6.47	AC50	340	nM	CHEMBL_ACT_25143627
SLC6A2	6.44	Kd	360	nM	CHEMBL_ACT_148574
SLC6A3	6.44	Kd	360	nM	CHEMBL_ACT_148575
HRH1	6.39	AC50	410	nM	CHEMBL_ACT_25212436
ADRA2C	6.2	AC50	630	nM	CHEMBL_ACT_25147802
HTR6	6.09	AC50	808	nM	CHEMBL_ACT_25118945
SLC6A3	6.08	AC50	830	nM	CHEMBL_ACT_25123878
ADRA1A	6.08	AC50	833.3	nM	CHEMBL_ACT_25137885
KCNH2	6.05	AC50	890	nM	CHEMBL_ACT_25117763
CYP3A4	6	Ki	1000	nM	CHEMBL_ACT_12163649
ACHE	5.98	IC50	1037	nM	CHEMBL_ACT_18570059
HTR2B	5.96	AC50	1100	nM	CHEMBL_ACT_25227455

Target pathways

Aggregated over 4 target gene(s): CYP3A4, HTR2A, SLC6A2, SLC6A4.

Top Reactome pathways

27 total, by targets touching each:

Pathway	Targets	Genes
SLC-mediated transport of neurotransmitters	2	SLC6A2, SLC6A4
Neurotransmitter clearance	1	SLC6A4
Transmission across Chemical Synapses	1	SLC6A4
Neuronal System	1	SLC6A4
Signal Transduction	1	HTR2A
Disease	1	SLC6A2
Phase I - Functionalization of compounds	1	CYP3A4
Xenobiotics	1	CYP3A4
Signaling by GPCR	1	HTR2A
Class A/1 (Rhodopsin-like receptors)	1	HTR2A
Amine ligand-binding receptors	1	HTR2A
Serotonin clearance from the synaptic cleft	1	SLC6A4
Transport of small molecules	1	SLC6A2
GPCR downstream signalling	1	HTR2A
Serotonin receptors	1	HTR2A
G alpha (q) signalling events	1	HTR2A
R-HSA-425366	1	SLC6A2
SLC-mediated transmembrane transport	1	SLC6A2
GPCR ligand binding	1	HTR2A
Aflatoxin activation and detoxification	1	CYP3A4
SLC transporter disorders	1	SLC6A2
Defective SLC6A2 causes orthostatic intolerance (OI)	1	SLC6A2
Disorders of transmembrane transporters	1	SLC6A2
Biosynthesis of maresin-like SPMs	1	CYP3A4
Aspirin ADME	1	CYP3A4
Atorvastatin ADME	1	CYP3A4
Prednisone ADME	1	CYP3A4

Dominant GO biological processes

GO term	Targets
response to xenobiotic stimulus	3
chemical synaptic transmission	2
memory	2
behavioral response to cocaine	2
neurotransmitter transport	2
amino acid transport	2
obsolete monoamine transport	2
sodium ion transmembrane transport	2
transmembrane transport	2
neurotransmitter reuptake	2
lipid hydroxylation	1
lipid metabolic process	1
steroid catabolic process	1
xenobiotic metabolic process	1
steroid metabolic process	1

Indications & clinical

Indications

3 indications (1 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
depressive disorder	4	MONDO:0002050	MONDO:0002009
cocaine dependence	3	MONDO:0005186	EFO:0002610
cannabis dependence	2	MONDO:0005689	EFO:0007191

Clinical trials

Total trials: 5.

Phase distribution

Phase	Trials
PHASE2	3
PHASE4	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00231348	PHASE4	COMPLETED	Nefazodone in the Treatment of Social Phobia
NCT00000293	PHASE3	COMPLETED	Effect of Nefazodone on Relapse in Females With Cocaine Abuse - 10
NCT00000286	PHASE2	COMPLETED	Effects of Nefazodone on Treatment of Female Cocaine Abusers - 3
NCT00015210	PHASE2	COMPLETED	Nefazodone in the Treatment of Cocaine Dependence and Depression - 4
NCT00249509	PHASE2	COMPLETED	Effectiveness of Nefazodone and Bupropion in Treating Marijuana Dependent Individuals

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 4 clinical and 3 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

1,138 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
AMITRIPTYLINE	ChEMBL + PubChem	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
DIHYDROERGOTAMINE	ChEMBL + PubChem	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
GENTIAN VIOLET	ChEMBL + PubChem	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
Pimavanserin	ChEMBL + PubChem	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
AMIODARONE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
AMOXAPINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
ATOMOXETINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
AZELASTINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
BEPRIDIL	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
BROMPERIDOL	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
CINNARIZINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
CLEMASTINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
CLOMIPRAMINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
CLOTRIMAZOLE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
CLOZAPINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
DESIPRAMINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
DIETHYLSTILBESTROL	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
DOMPERIDONE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
DULOXETINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
FLUOXETINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
FLUPHENAZINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
FLUSPIRILENE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
HALOPERIDOL	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
KETOCONAZOLE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
LOXAPINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
MEBEVERINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
MEFLOQUINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
NITAZOXANIDE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
NOMIFENSINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
NORTRIPTYLINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
OXICONAZOLE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
PAROXETINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
PERHEXILINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
PERPHENAZINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
PIMOZIDE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
PONATINIB	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
PROCHLORPERAZINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
PROPAFENONE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
RALOXIFENE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
SERTRALINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
SULCONAZOLE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
TERCONAZOLE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
TERFENADINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
THIORIDAZINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
THIOTEPA	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
TRIFLUOPERAZINE	ChEMBL	Phase 4 (approved)	CYP3A4, HTR2A, SLC6A2, SLC6A4
ZUCLOPENTHIXOL	ChEMBL	Phase 3	CYP3A4, HTR2A, SLC6A2, SLC6A4
BENZETHONIUM CHLORIDE	ChEMBL	Phase 2	CYP3A4, HTR2A, SLC6A2, SLC6A4
METERGOLINE	ChEMBL	Phase 2	CYP3A4, HTR2A, SLC6A2, SLC6A4
OXATOMIDE	ChEMBL	Phase 2	CYP3A4, HTR2A, SLC6A2, SLC6A4
RITANSERIN	ChEMBL	Phase 2	CYP3A4, HTR2A, SLC6A2, SLC6A4
Bosentan	PubChem	Approved	CYP3A4, HTR2A, SLC6A2, SLC6A4
Linagliptin	PubChem	Approved	CYP3A4, HTR2A, SLC6A2, SLC6A4
Pyrazinamide	PubChem	Approved	CYP3A4, HTR2A, SLC6A2, SLC6A4
CRIZOTINIB	ChEMBL + PubChem	Phase 4 (approved)	HTR2A, SLC6A2, SLC6A4
FIDAXOMICIN	ChEMBL + PubChem	Phase 4 (approved)	HTR2A, SLC6A2, SLC6A4
OLODATEROL	ChEMBL + PubChem	Phase 4 (approved)	HTR2A, SLC6A2, SLC6A4
PODOFILOX	ChEMBL + PubChem	Phase 4 (approved)	CYP3A4, SLC6A2, SLC6A4