Pimozide

Summary

Pimozide (CHEMBL1423) is an approved small-molecule H1-receptor antagonist (ATC N05AG02) targeting HTR6, HTR7, and HTR1A; indicated across 8 conditions including psychotic disorder and tourette syndrome.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N05AG02
• Targets: 12 (HTR6, HTR7, HTR1A…)
• Indications: 8 conditions
• Clinical trials: 10
• Chemistry: 461.5 Da · C28H29F2N3O

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1423
Name	Pimozide
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	16362
ChEBI	CHEBI:8212
ATC	N05AG02
Molecular formula	C28H29F2N3O
Molecular weight	461.5
InChIKey	YVUQSNJEYSNKRX-UHFFFAOYSA-N

SMILES: C1CN(CCC1N2C3=CC=CC=C3NC2=O)CCCC(C4=CC=C(C=C4)F)C5=CC=C(C=C5)F

IUPAC name: 3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1H-benzimidazol-2-one

ChEBI definition: A member of the class of benzimidazoles that is 1,3-dihydro-2H-benzimidazol-2-one in which one of the nitrogens is substituted by a piperidin-4-yl group, which in turn is substituted on the nitrogen by a 4,4-bis(p-fluorophenyl)butyl group.

Pharmacological roles (ChEBI): H1-receptor antagonist, serotonergic antagonist, first generation antipsychotic, antidyskinesia agent, dopaminergic antagonist.

Also known as: MCN-JR-6238, NSC-170984, Orap, Pimozida, Pimozide, R 623, R 6238, R-623, R-6238, SID11111615, SID11112507, SID11113804

Patent coverage: 4,540 distinct patent families (17,310 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 17,275 (100%) 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
HTR6	5-HT6 receptor	Antagonist	7.2	0.2%	P50406
HTR7	5-HT7 receptor	Antagonist	9.3	0.8%	P34969
HTR1A	5-HT1A receptor	Antagonist	6.8	0%	P08908
DRD2	D2 receptor	Antagonist	8.8	0%	P14416
DRD3	D3 receptor	Antagonist	8.6	0%	P35462
HRH1	H1 receptor	Antagonist	6.2	0%	P35367
KCNJ6	Kir3.2	Antagonist	5.5	0.1%	P48051
CACNA1G	Cav3.1	Antagonist	7.5	4%	O43497
CACNA1H	Cav3.2	Pore blocker	6.8	0.2%	O95180
CACNA1I	Cav3.3	Antagonist	7.5	0%	Q9P0X4
KCNA10	Kv1.8		6.5	15.2%	Q16322
HTR2A	5-HT2A receptor	Antagonist	7.7	0%	P28223

Broader ChEMBL bioactivity targets: 98 (assay-derived). Sample: Tyrosyl-DNA phosphodiesterase 1, Microtubule-associated protein tau, Lysine-specific demethylase 4E, Ubiquitin carboxyl-terminal hydrolase 2, Nuclear receptor ROR-gamma, Survival motor neuron protein, Prelamin-A/C, RecQ-like DNA helicase BLM, Inositol monophosphatase 1, 4’-phosphopantetheinyl transferase ffp.

Bioactivity

ChEMBL activities: 118 potent at pChembl ≥ 5 of 198 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P18901	9.4	IC50	0.4	nM	CHEMBL_ACT_1074892
P18901	9.32	IC50	0.48	nM	CHEMBL_ACT_1091814
P32305	9.3	Ki	0.5	nM	CHEMBL_ACT_75948
P20288	9.22	Ki	0.6	nM	CHEMBL_ACT_715198
DRD2	8.85	Ki	1.4	nM	CHEMBL_ACT_25580232
DRD3	8.6	Ki	2.5	nM	CHEMBL_ACT_25580233
HTR2A	8.57	IC50	2.7	nM	CHEMBL_ACT_25580236
DRD3	8.52	AC50	3	nM	CHEMBL_ACT_25194604
KCNH2	8.52	IC50	3.02	nM	CHEMBL_ACT_2616651
P97697	8.1	Potency	7.9	nM	CHEMBL_ACT_4880424
DRD2	7.93	Ki	11.7	nM	CHEMBL_ACT_12174016
DRD2	7.92	Ki	12	nM	CHEMBL_ACT_927110
KCNH2	7.9	AC50	12.6	nM	CHEMBL_ACT_25117777
DRD2	7.8	AC50	16	nM	CHEMBL_ACT_25140264
KCNH2	7.75	IC50	18	nM	CHEMBL_ACT_326801
KCNH2	7.75	IC50	18	nM	CHEMBL_ACT_784656
KCNH2	7.75	IC50	18	nM	CHEMBL_ACT_927111
KCNH2	7.74	IC50	18.2	nM	CHEMBL_ACT_1429720
KCNH2	7.74	IC50	18.2	nM	CHEMBL_ACT_2645528
KCNH2	7.7	IC50	20	nM	CHEMBL_ACT_15257967
DRD3	7.55	AC50	28	nM	CHEMBL_ACT_25193459
DRD2	7.54	Kd	29	nM	CHEMBL_ACT_3408908
CACNA1G	7.4	Kd	40	nM	CHEMBL_ACT_5126723
KCNH2	7.38	Ki	42	nM	CHEMBL_ACT_1794639
HTR2A	7.31	AC50	48.6	nM	CHEMBL_ACT_25173592
KCNH2	7.3	IC50	50.12	nM	CHEMBL_ACT_1053113
KCNH2	7.3	IC50	50.12	nM	CHEMBL_ACT_1523566
KCNH2	7.3	IC50	50.12	nM	CHEMBL_ACT_2358285
SCN1A	7.27	IC50	54	nM	CHEMBL_ACT_15257908
KCNH2	7.26	IC50	54.6	nM	CHEMBL_ACT_2295021

Target pathways

Aggregated over 12 target gene(s): HTR6, HTR7, HTR1A, DRD2, DRD3, HRH1, KCNJ6, CACNA1G, CACNA1H, CACNA1I, KCNA10, HTR2A.

Top Reactome pathways

35 total, by targets touching each:

Pathway	Targets	Genes
Signal Transduction	4	HTR1A, HTR2A, HTR6, HTR7
Signaling by GPCR	4	HTR1A, HTR2A, HTR6, HTR7
Class A/1 (Rhodopsin-like receptors)	4	HTR1A, HTR2A, HTR6, HTR7
Amine ligand-binding receptors	4	HTR1A, HTR2A, HTR6, HTR7
Serotonin receptors	4	HTR1A, HTR2A, HTR6, HTR7
GPCR ligand binding	4	HTR1A, HTR2A, HTR6, HTR7
Developmental Biology	3	CACNA1G, CACNA1H, CACNA1I
NCAM signaling for neurite out-growth	3	CACNA1G, CACNA1H, CACNA1I
GPCR downstream signalling	3	HTR2A, HTR6, HTR7
Muscle contraction	3	CACNA1G, CACNA1H, CACNA1I
NCAM1 interactions	3	CACNA1G, CACNA1H, CACNA1I
Axon guidance	3	CACNA1G, CACNA1H, CACNA1I
Smooth Muscle Contraction	3	CACNA1G, CACNA1H, CACNA1I
Nervous system development	3	CACNA1G, CACNA1H, CACNA1I
Neuronal System	2	KCNA10, KCNJ6
Potassium Channels	2	KCNA10, KCNJ6
Dopamine receptors	2	DRD2, DRD3
G alpha (q) signalling events	2	HRH1, HTR2A
G alpha (s) signalling events	2	HTR6, HTR7
Neurotransmitter receptors and postsynaptic signal transmission	1	KCNJ6
Transmission across Chemical Synapses	1	KCNJ6
Activation of G protein gated Potassium channels	1	KCNJ6
G protein gated Potassium channels	1	KCNJ6
Inwardly rectifying K+ channels	1	KCNJ6
Voltage gated Potassium channels	1	KCNA10
Histamine receptors	1	HRH1
G alpha (i) signalling events	1	DRD3
Cellular responses to stimuli	1	CACNA1H
RHOBTB3 ATPase cycle	1	HTR7
GABA receptor activation	1	KCNJ6

Dominant GO biological processes

GO term	Targets
signal transduction	8
G protein-coupled receptor signaling pathway	7
chemical synaptic transmission	6
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	5
monoatomic ion transport	5
monoatomic ion transmembrane transport	5
G protein-coupled serotonin receptor signaling pathway	4
transmembrane transport	4
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	3
intracellular calcium ion homeostasis	3
visual learning	3
response to xenobiotic stimulus	3
regulation of dopamine secretion	3
response to cocaine	3
behavioral response to cocaine	3

Indications & clinical

Indications

8 indications (3 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
psychotic disorder	4	MONDO:0005485	EFO:0005407
Tourette syndrome	4	MONDO:0007661	EFO:0004895
anxiety	3	MONDO:0011918	EFO:0005230
dementia	3	MONDO:0001627	HP:0000726
depressive disorder	3	MONDO:0002050	MONDO:0002050
amyotrophic lateral sclerosis	2	MONDO:0004976	MONDO:0004976

2 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 10.

Phase distribution

Phase	Trials
PHASE2	4
PHASE4	2
Not specified	2
PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT02307396	PHASE4	COMPLETED	Evaluation of the Necessity of Long-term Pharmacological Treatment With Antipsychotics in Schizophrenic Patients
NCT02374567	PHASE3	TERMINATED	Pharmacovigilance in Gerontopsychiatric Patients
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00374244	PHASE2	COMPLETED	Efficacy of Pimozide Augmentation for Clozapine Partial Response
NCT03272503	PHASE2	UNKNOWN	A Clinical Trial of Pimozide in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT05716854	PHASE1	COMPLETED	Electrophysiological Effects of Potential QT Prolonging Drugs
NCT02600741	Not specified	COMPLETED	Family Intervention in Recent Onset Schizophrenia Treatment (FIRST)
NCT05507372	Not specified	UNKNOWN	Treatment for Post Acute COVID-19 Syndrome

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

PharmGKB dosing guidelines (1) — CPIC / DPWG genotype-guided dosing for this drug (drug × pharmacogene):

Guideline	Source	Gene(s)	Dosing	Recommendation
Annotation of DPWG Guideline for pimozide and CYP2D6	DPWG	CYP2D6	yes	yes

PharmGKB also curates 0 clinical and 6 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.

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

Molecule	Source	Status	Shared targets
FLUNARIZINE	ChEMBL	Phase 2	CACNA1G, CACNA1H, CACNA1I, DRD2, DRD3, HRH1, HTR1A, HTR2A
BREXPIPRAZOLE	ChEMBL + PubChem	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
DIHYDROERGOTAMINE	ChEMBL + PubChem	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
AMOXAPINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
CARIPRAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
CINACALCET	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
CLOZAPINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
CYPROHEPTADINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
DIBENZEPIN	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
DOXEPIN	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
FLUPHENAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
HALOPERIDOL	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
IMIPRAMINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
KETANSERIN	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
LOXAPINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
METHYSERGIDE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
MIANSERIN	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
NEFAZODONE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
OLANZAPINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
PROMAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
QUETIAPINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
RISPERIDONE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
THIORIDAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
THIOTHIXENE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
ZIPRASIDONE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
FANANSERIN	ChEMBL	Phase 2	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
LYSERGIDE	ChEMBL	Phase 2	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
METERGOLINE	ChEMBL	Phase 2	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
PENFLURIDOL	ChEMBL	Phase 2	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
RITANSERIN	ChEMBL	Phase 2	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
SPIPERONE	ChEMBL	Phase 2	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
SPIRAMIDE	ChEMBL	Phase 2	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
Pyrazinamide	PubChem	Approved	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6, HTR7
DESLORATADINE	ChEMBL + PubChem	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
PRAMIPEXOLE	ChEMBL + PubChem	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR7
TAMSULOSIN	ChEMBL + PubChem	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR7
AMITRIPTYLINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
ASENAPINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
AZELASTINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR2A, HTR6, HTR7
BUSPIRONE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR7
CARVEDILOL	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HTR1A, HTR2A, HTR6, HTR7
CISAPRIDE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR7
CLEMASTINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
CLOMIPRAMINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
EBASTINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
HYDROXYZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR2A, HTR6, HTR7
ILOPERIDONE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
IPRINDOLE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
KETOTIFEN	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR2A, HTR6, HTR7
LURASIDONE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR7
MAPROTILINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
METHYLERGONOVINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
NORTRIPTYLINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
PERGOLIDE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
PERPHENAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR7
PROCHLORPERAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6
PROMETHAZINE	ChEMBL	Phase 4 (approved)	DRD2, DRD3, HRH1, HTR1A, HTR2A, HTR6