Diphenhydramine

Summary

Diphenhydramine (CHEMBL657) is an approved small-molecule H1-receptor antagonist (ATC D04AA32) targeting HRH1; indicated across 63 conditions including allergic disease and plasma cell myeloma.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: D04AA32 (+2 more)
• Targets: 1 (HRH1)
• Indications: 63 conditions
• Clinical trials: 154
• Chemistry: 255.35 Da · C17H21NO

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL657
Name	Diphenhydramine
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	3100
ChEBI	CHEBI:4636
ATC	D04AA32, R06AA52, R06AA02
Molecular formula	C17H21NO
Molecular weight	255.35
InChIKey	ZZVUWRFHKOJYTH-UHFFFAOYSA-N

SMILES: CN(C)CCOC(C1=CC=CC=C1)C2=CC=CC=C2

IUPAC name: 2-benzhydryloxy-N,N-dimethylethanamine

ChEBI definition: An ether that is the benzhydryl ether of 2-(dimethylamino)ethanol. It is a H1-receptor antagonist used as a antipruritic and antitussive drug.

Pharmacological roles (ChEBI): H1-receptor antagonist, antiemetic, sedative, anti-allergic agent, muscarinic antagonist, antiparkinson drug, antipruritic drug, local anaesthetic, antidyskinesia agent, antitussive, oneirogen.

Also known as: Difenhidramina, Diphenhdyra, Diphenhydramine, Restamin, diphenhydramine, SID11111059, SID11111060, SID26751623, SID90341811, SID104171144, SID50100219, SID50104292

Parent form; salt/anhydrous children: CHEMBL1620, CHEMBL1201089

Patent coverage: 44,048 distinct patent families (99,674 SureChEMBL compound mentions), from 1 matched compound structure(s). 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
HRH1	H1 receptor	Antagonist	7.9	0%	P35367

Broader ChEMBL bioactivity targets: 36 (assay-derived). Sample: Prelamin-A/C, 4’-phosphopantetheinyl transferase ffp, Thrombopoietin, Solute carrier family 22 member 2, Muscarinic acetylcholine receptor M4, 5-hydroxytryptamine receptor 2B, Alpha-2A adrenergic receptor, Histamine H2 receptor, Alpha-2B adrenergic receptor, Thyrotropin receptor.

Bioactivity

ChEMBL activities: 57 potent at pChembl ≥ 5 of 87 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P31389	9	IC50	1	nM	CHEMBL_ACT_429899
P31389	7.93	Kd	11.75	nM	CHEMBL_ACT_7846167
HRH1	7.83	Ki	14.79	nM	CHEMBL_ACT_7846197
HRH1	7.7	Ki	20	nM	CHEMBL_ACT_7681414
HRH1	7.5	AC50	32	nM	CHEMBL_ACT_25212872
CHRM4	7.28	Ki	52	nM	CHEMBL_ACT_7681448
THPO	7.2	Potency	63.1	nM	CHEMBL_ACT_4809322
THPO	7.2	Potency	63.1	nM	CHEMBL_ACT_5070333
CHRM1	7.08	Ki	83	nM	CHEMBL_ACT_7681442
CHRM5	6.94	Ki	116	nM	CHEMBL_ACT_7681450
CHRM3	6.86	Ki	137	nM	CHEMBL_ACT_7681446
CHRM5	6.79	IC50	162	nM	CHEMBL_ACT_7681449
HRH1	6.77	IC50	171	nM	CHEMBL_ACT_7681413
P08482	6.7	Potency	199.5	nM	CHEMBL_ACT_4803427
HRH2	6.6	AC50	252.2	nM	CHEMBL_ACT_25114529
CHRM1	6.46	IC50	346	nM	CHEMBL_ACT_7681441
CHRM2	6.43	Ki	373	nM	CHEMBL_ACT_7681444
CHRM4	6.43	IC50	372	nM	CHEMBL_ACT_7681447
HTR2A	6.43	Ki	370	nM	CHEMBL_ACT_7681524
HTR2C	6.29	Ki	513	nM	CHEMBL_ACT_7681528
CHRM5	6.23	AC50	590.9	nM	CHEMBL_ACT_25137465
CHRM3	6.19	IC50	647	nM	CHEMBL_ACT_7681445
HTR2B	6.18	AC50	667.4	nM	CHEMBL_ACT_25164208
HTR2B	6.15	Ki	711	nM	CHEMBL_ACT_7681526
CHRM2	6.09	AC50	813.3	nM	CHEMBL_ACT_25196111
HTR2C	6.08	AC50	830	nM	CHEMBL_ACT_25132150
HTR2A	6.06	AC50	874.6	nM	CHEMBL_ACT_25173735
HTR2C	6.01	IC50	980	nM	CHEMBL_ACT_7681527
CHRM2	5.98	IC50	1050	nM	CHEMBL_ACT_7681443
HTR2B	5.95	IC50	1118	nM	CHEMBL_ACT_7681525

Target pathways

Aggregated over 1 target gene(s): HRH1.

Top Reactome pathways

2 total, by targets touching each:

Pathway	Targets	Genes
Histamine receptors	1	HRH1
G alpha (q) signalling events	1	HRH1

Dominant GO biological processes

GO term	Targets
inflammatory response	1
G protein-coupled receptor signaling pathway	1
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
chemical synaptic transmission	1
memory	1
visual learning	1
regulation of vascular permeability	1
positive regulation of vasoconstriction	1
regulation of synaptic plasticity	1
cellular response to histamine	1
signal transduction	1
phospholipase C-activating serotonin receptor signaling pathway	1

Indications & clinical

Indications

63 indications (2 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
allergic disease	4	MONDO:0005271	MONDO:0005271
plasma cell myeloma	3	MONDO:0009693	EFO:0001378
kidney disorder	3	MONDO:0005240	EFO:0003086
anxiety	3	MONDO:0011918	EFO:0005230
urticaria	3	MONDO:0005492	EFO:0005531
lupus nephritis	3	MONDO:0005556	EFO:0005761
dementia	3	MONDO:0001627	HP:0000726
rhinitis	3	MONDO:0003014	EFO:0008521
stomatitis	3	MONDO:0004842	EFO:0009688
depressive disorder	3	MONDO:0002050	MONDO:0002050
primary progressive multiple sclerosis	3	MONDO:0000451	EFO:0008520
migraine disorder	3	MONDO:0005277	MONDO:0005277
systemic lupus erythematosus	3	MONDO:0007915	MONDO:0007915
multiple sclerosis	3	MONDO:0005301	MONDO:0005301
neoplasm of mature B-cells	2	MONDO:0004949	EFO:0000096
lymphoma	2	MONDO:0005062	EFO:0000574
neoplasm	2	MONDO:0005070	EFO:0000616
renal cell carcinoma	2	MONDO:0005086	EFO:0000681
cocaine dependence	2	MONDO:0005186	EFO:0002610
canker sore	2	MONDO:0005318	EFO:0003938
chronic hepatitis B virus infection	2	MONDO:0005366	EFO:0004239
restless legs syndrome	2	MONDO:0005391	EFO:0004270
graft versus host disease	2	MONDO:0013730	EFO:0004599
non-Hodgkin lymphoma	2	MONDO:0018908	EFO:0005952
mast cell leukemia	2	MONDO:0020334	EFO:0007359
acute lymphoblastic leukemia	2	MONDO:0004967	EFO:0000220
diffuse large B-cell lymphoma	2	MONDO:0018905	EFO:0000403
non-small cell lung carcinoma	2	MONDO:0005233	EFO:0003060
T-cell leukemia	2	MONDO:0005525	EFO:0005592
gastric neoplasm	2	MONDO:0021085	MONDO:0001056
endometrium neoplasm	2	MONDO:0021251	MONDO:0011962
acute myeloid leukemia	2	MONDO:0018874	EFO:0000222
breast carcinoma in situ	2	MONDO:0004658	MONDO:0004658
myelodysplastic syndrome	2	MONDO:0018881	EFO:0000198
autism	2	MONDO:0005260	EFO:0003758
alcohol abuse	2	MONDO:0002046	MONDO:0007079
breast carcinoma	2	MONDO:0004989	EFO:0000305
gastric adenocarcinoma	2	MONDO:0005036	EFO:0000503
hairy cell leukemia	2	MONDO:0018935	EFO:1000956
breast neoplasm	2	MONDO:0021100	MONDO:0007254
follicular lymphoma	2	MONDO:0018906	MONDO:0018906
Crohn disease	1	MONDO:0005011	EFO:0000384
immune system disorder	1	MONDO:0005046	EFO:0000540
major depressive disorder	1	MONDO:0002009	MONDO:0002009
lung neoplasm	1	MONDO:0021117	MONDO:0008903
autoimmune thrombocytopenic purpura	1	MONDO:0008558	EFO:0007160
mesothelioma	1	MONDO:0005065	EFO:0000588
alpha 1-antitrypsin deficiency	1	MONDO:0013282	MONDO:0013282
atopic eczema	0	MONDO:0004980	EFO:0000274

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

Clinical trials

Total trials: 154.

Phase distribution

Phase	Trials
PHASE2	45
PHASE1	27
PHASE4	21
PHASE3	21
Not specified	21
PHASE1/PHASE2	12
PHASE2/PHASE3	5
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07542730	PHASE4	NOT_YET_RECRUITING	Diphenhydramine as an Adjunct to Moderate Sedation for Procedural First Trimester Abortions
NCT07542756	PHASE4	NOT_YET_RECRUITING	A SMART Approach to Evaluating the Benefits of Common Prescription and OTC Medications for Insomnia
NCT00475306	PHASE4	COMPLETED	The Montefiore Metoclopramide Study
NCT00638443	PHASE4	COMPLETED	Lumbar Stenosis Outcomes Research (LUSTOR)
NCT00648973	PHASE4	COMPLETED	To Determine if Diphenhydramine Works for Nasal Congestion at Two Different Doses
NCT00937924	PHASE4	COMPLETED	Adjunct Sedatives in Endoscopic Ultrasound (EUS) and Endoscopic Retrograde Cholangiopancreatography (ERCP) Procedures
NCT01825941	PHASE4	COMPLETED	Diphenhydramine for Acute Migraine
NCT01967433	PHASE4	COMPLETED	Diphenhydramine as an Adjunctive Sedative in Patients on Chronic Opioids
NCT01985789	PHASE4	COMPLETED	Anti-histamines and Methacholine Challenges.
NCT02062710	PHASE4	COMPLETED	Antitussive Effect of a Naturally Flavored Syrup Containing Diphenhydramine, Compared With Dextromethorphan and Placebo
NCT02098499	PHASE4	WITHDRAWN	Haldol/Diphenhydramine Versus Metoclopramide/Diphenhydramine for Treatment of Acute Headache in the ED: A RCT
NCT02339155	PHASE4	COMPLETED	Effect of Raxibacumab on Immunogenicity of Anthrax Vaccine Adsorbed
NCT02389829	PHASE4	COMPLETED	Hydromorphone Versus Prochlorperazine + Diphenhydramine for Acute Migraine
NCT02463929	PHASE4	COMPLETED	Dyphenhidramine Effect on Prevention of Sevoflurane Induced Post Anesthesia Agitation in Pediatric
NCT02657031	PHASE4	COMPLETED	The CHECK Trial: A Comparison of Headache Treatment in the ED: Compazine Versus Ketamine
NCT02972502	PHASE4	TERMINATED	Efficacy of Haloperidol vs. Metoclopramide for Treatment of Acute Headaches and Migraines in the Emergency Department
NCT03968939	PHASE4	COMPLETED	Total Joint Arthroplasty and Sleep
NCT05586477	PHASE4	COMPLETED	Diphenhydramine and Sweating
NCT06019728	PHASE4	COMPLETED	A Prospective Study to Investigate Safety and Tolerability of Shorter Infusion of Fabrazyme
NCT06217367	PHASE4	UNKNOWN	Over-the-Counter Antihistamines & Heat Stress
NCT06310642	PHASE4	COMPLETED	Efficacy of Prophylactic Treatment of Oral Prochlorperazine for Acute Mountain Sickness
NCT04221477	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Obinutuzumab in Participants With ISN/RPS 2003 Class III or IV Lupus Nephritis
NCT04629248	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy and Safety of Obinutuzumab in Participants With Primary Membranous Nephropathy
NCT05405166	PHASE3	ACTIVE_NOT_RECRUITING	SC Versus IV Isatuximab in Combination With Pomalidomide and Dexamethasone in RRMM
NCT06702670	PHASE2/PHASE3	RECRUITING	Anticholinergics for Cervical Edema in Labor
NCT06704620	PHASE3	NOT_YET_RECRUITING	Study of Tislelizumab and Platinum-based Chemotherapy Combination With H1 Receptor Antagonist（Diphenhydramine）in Advanced and Metastatic Non-Small Cell Lung Cancer
NCT06819774	PHASE3	RECRUITING	Phase III Clinical Study of Cetirizine Hydrochloride Injection in Treatment of Acute Urticaria
NCT06910241	PHASE3	RECRUITING	Lidocaine Versus Diphenhydramine to Achieve Local Anesthesia for Laceration Repairs
NCT07472413	PHASE3	NOT_YET_RECRUITING	Alternate Pre-med in Anti-Cluster of Differentiation 20 (CD20) Pilot Project
NCT07570173	PHASE2/PHASE3	RECRUITING	A Clinical Trial of MK-1045 in People With B-cell Acute Lymphoblastic Leukemia (MK-1045-005)
NCT00137969	PHASE2/PHASE3	COMPLETED	A Study to Evaluate the Safety of Rituximab Retreatment in Subjects With Systemic Lupus Erythematosus
NCT00282347	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Class III or IV Lupus Nephritis
NCT00381810	PHASE3	TERMINATED	A Study to Evaluate the Safety of Rituximab Retreatment in Subjects With Systemic Lupus Erythematosus
NCT00682734	PHASE3	COMPLETED	Metoclopramide for Migraine: A Dose Finding Study
NCT01177852	PHASE3	WITHDRAWN	Evaluation of Efficacy and Safety in Control Cough and the Relief of Nasal Symptoms in Children 2-12 Years Old,Suffering From Cough and Acute Rhinitis
NCT01264939	PHASE3	COMPLETED	A Safety Study of Xolair (Omalizumab) in Patients With Chronic Idiopathic Urticaria (CIU) Who Remain Symptomatic Despite Treatment With H1 Antihistamines, H2 Blockers, and/or Leukotriene Receptor Antagonists
NCT01837446	PHASE2/PHASE3	COMPLETED	Morphine Mouthwash for Management of Oral Mucositis in Patients With Head and Neck Cancer
NCT01858090	PHASE3	COMPLETED	Intrathecal Levobupivacaine With Opioids for Caesarean Section
NCT02023164	PHASE3	COMPLETED	Pilot Phase III Clinical Trial of JDP-205 IV Injection for Treatment of Acute Urticaria
NCT02374567	PHASE3	TERMINATED	Pharmacovigilance in Gerontopsychiatric Patients

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 7 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.

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

Molecule	Source	Status	Shared targets
ACLIDINIUM BROMIDE	ChEMBL + PubChem	Phase 4 (approved)	HRH1
DESLORATADINE	ChEMBL + PubChem	Phase 4 (approved)	HRH1
DIHYDROERGOTAMINE	ChEMBL + PubChem	Phase 4 (approved)	HRH1
PALIPERIDONE	ChEMBL + PubChem	Phase 4 (approved)	HRH1
PRAMIPEXOLE	ChEMBL + PubChem	Phase 4 (approved)	HRH1
ABEMACICLIB	ChEMBL	Phase 4 (approved)	HRH1
ACETOPHENAZINE	ChEMBL	Phase 4 (approved)	HRH1
ACRIVASTINE	ChEMBL	Phase 4 (approved)	HRH1
AMIODARONE	ChEMBL	Phase 4 (approved)	HRH1
AMISULPRIDE	ChEMBL	Phase 4 (approved)	HRH1
AMITRIPTYLINE	ChEMBL	Phase 4 (approved)	HRH1
AMOXAPINE	ChEMBL	Phase 4 (approved)	HRH1
AMSACRINE	ChEMBL	Phase 4 (approved)	HRH1
ANTAZOLINE	ChEMBL	Phase 4 (approved)	HRH1
APOMORPHINE	ChEMBL	Phase 4 (approved)	HRH1
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	HRH1
ASENAPINE	ChEMBL	Phase 4 (approved)	HRH1
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	HRH1
ATOMOXETINE	ChEMBL	Phase 4 (approved)	HRH1
AZATADINE	ChEMBL	Phase 4 (approved)	HRH1
AZELASTINE	ChEMBL	Phase 4 (approved)	HRH1
BENFLUOREX	ChEMBL	Phase 4 (approved)	HRH1
BENPERIDOL	ChEMBL	Phase 4 (approved)	HRH1
BENZBROMARONE	ChEMBL	Phase 4 (approved)	HRH1
BENZTROPINE	ChEMBL	Phase 4 (approved)	HRH1
BEPRIDIL	ChEMBL	Phase 4 (approved)	HRH1
BETAMETHASONE PHOSPHORIC ACID	ChEMBL	Phase 4 (approved)	HRH1
BIPERIDEN	ChEMBL	Phase 4 (approved)	HRH1
BREXPIPRAZOLE	ChEMBL	Phase 4 (approved)	HRH1
BROMPERIDOL	ChEMBL	Phase 4 (approved)	HRH1
BROMPHENIRAMINE	ChEMBL	Phase 4 (approved)	HRH1
BUCLIZINE	ChEMBL	Phase 4 (approved)	HRH1
BUPROPION	ChEMBL	Phase 4 (approved)	HRH1
BUSPIRONE	ChEMBL	Phase 4 (approved)	HRH1
BUTRIPTYLINE	ChEMBL	Phase 4 (approved)	HRH1
CABERGOLINE	ChEMBL	Phase 4 (approved)	HRH1
CANDESARTAN CILEXETIL	ChEMBL	Phase 4 (approved)	HRH1
CAPTOPRIL	ChEMBL	Phase 4 (approved)	HRH1
CARBINOXAMINE	ChEMBL	Phase 4 (approved)	HRH1
CARIPRAZINE	ChEMBL	Phase 4 (approved)	HRH1
CETIRIZINE	ChEMBL	Phase 4 (approved)	HRH1
CHLORDIAZEPOXIDE	ChEMBL	Phase 4 (approved)	HRH1
CHLORPHENIRAMINE	ChEMBL	Phase 4 (approved)	HRH1
CHLORPHENTERMINE	ChEMBL	Phase 4 (approved)	HRH1
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	HRH1
CHLORPROTHIXENE	ChEMBL	Phase 4 (approved)	HRH1
CINACALCET	ChEMBL	Phase 4 (approved)	HRH1
CINNARIZINE	ChEMBL	Phase 4 (approved)	HRH1
CISAPRIDE	ChEMBL	Phase 4 (approved)	HRH1
CITALOPRAM	ChEMBL	Phase 4 (approved)	HRH1
CLEMASTINE	ChEMBL	Phase 4 (approved)	HRH1
CLOFAZIMINE	ChEMBL	Phase 4 (approved)	HRH1
CLOMIPRAMINE	ChEMBL	Phase 4 (approved)	HRH1
CLOTRIMAZOLE	ChEMBL	Phase 4 (approved)	HRH1
CLOZAPINE	ChEMBL	Phase 4 (approved)	HRH1
CYCLIZINE	ChEMBL	Phase 4 (approved)	HRH1
CYCLOBENZAPRINE	ChEMBL	Phase 4 (approved)	HRH1
CYPROHEPTADINE	ChEMBL	Phase 4 (approved)	HRH1
DAUNORUBICIN	ChEMBL	Phase 4 (approved)	HRH1
DESIPRAMINE	ChEMBL	Phase 4 (approved)	HRH1