Hydrochlorothiazide

Summary

Hydrochlorothiazide (CHEMBL435) is an approved small-molecule diuretic (ATC C03AX01) targeting NAPEPLD and SLC12A3; indicated across 26 conditions including hypertensive disorder and cardiovascular disorder.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: C03AX01 (+1 more)
• Targets: 2 (NAPEPLD, SLC12A3)
• Indications: 26 conditions
• Clinical trials: 237
• Chemistry: 297.7 Da · C7H8ClN3O4S2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL435
Name	Hydrochlorothiazide
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	3639
ChEBI	CHEBI:5778
ATC	C03AX01, C03AA03
Molecular formula	C7H8ClN3O4S2
Molecular weight	297.7
InChIKey	JZUFKLXOESDKRF-UHFFFAOYSA-N

SMILES: C1NC2=CC(=C(C=C2S(=O)(=O)N1)S(=O)(=O)N)Cl

IUPAC name: 6-chloro-1,1-dioxo-3,4-dihydro-2H-1lambda6,2,4-benzothiadiazine-7-sulfonamide

ChEBI definition: A benzothiadiazine that is 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide substituted by a chloro group at position 6 and a sulfonamide at 7. It is diuretic used for the treatment of hypertension and congestive heart failure.

Pharmacological roles (ChEBI): diuretic, antihypertensive agent.

Other ChEBI roles (chemical / environmental): xenobiotic, environmental contaminant.

Also known as: Apo-hydro, Apresazide, Carozide, Chlorosulthiadil, Copalia-hct, Dafiro-hct, Dihydrochlorurite, Esidrex, Esidrix, Exforge-hct, Hidroclorotiazida, Hidrotiazida

Patent coverage: 12,709 distinct patent families (43,504 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 43,209 (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
NAPEPLD	N-Acylphosphatidylethanolamine-phospholipase D	Binding	5.1	0%	Q6IQ20
SLC12A3	Na-Cl symporter	Inhibition		0.2%	P55017

Broader ChEMBL bioactivity targets: 9 (assay-derived). Sample: Survival motor neuron protein, Prelamin-A/C, Peripheral myelin protein 22, 5-hydroxytryptamine receptor 2B, Thyroid hormone receptor beta, Carbonic anhydrase 2, Carbonic anhydrase 1, Cytochrome P450 2C9, DNA repair nuclease/redox regulator APEX1.

Bioactivity

ChEMBL activities: 47 potent at pChembl ≥ 5 of 50 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
LMNA	8.35	Potency	4.5	nM	CHEMBL_ACT_3667671
THRB	6.55	Potency	281.8	nM	CHEMBL_ACT_4017010
CA2	6.54	Ki	290	nM	CHEMBL_ACT_12161322
CA2	6.54	Ki	290	nM	CHEMBL_ACT_12655971
CA2	6.54	Ki	290	nM	CHEMBL_ACT_13286760
CA2	6.54	Ki	290	nM	CHEMBL_ACT_13866408
CA2	6.54	Ki	290	nM	CHEMBL_ACT_14661469
CA2	6.54	Ki	290	nM	CHEMBL_ACT_15108422
CA2	6.54	Ki	290	nM	CHEMBL_ACT_15143692
CA2	6.54	Ki	290	nM	CHEMBL_ACT_15170050
CA2	6.54	Ki	290	nM	CHEMBL_ACT_15177703
CA2	6.54	Ki	290	nM	CHEMBL_ACT_15674573
CA2	6.54	Ki	290	nM	CHEMBL_ACT_16390804
CA2	6.54	Ki	290	nM	CHEMBL_ACT_16415185
CA2	6.54	Ki	290	nM	CHEMBL_ACT_16451231
CA2	6.54	Ki	290	nM	CHEMBL_ACT_16478448
CA2	6.54	Ki	290	nM	CHEMBL_ACT_16520000
CA2	6.54	Ki	290	nM	CHEMBL_ACT_17997783
CA2	6.54	Ki	290	nM	CHEMBL_ACT_18160122
CA2	6.54	Ki	290	nM	CHEMBL_ACT_19413186
CA2	6.54	Ki	290	nM	CHEMBL_ACT_26047520
CA2	6.54	Ki	290	nM	CHEMBL_ACT_5297084
CA2	6.54	Ki	290	nM	CHEMBL_ACT_6320725
CA2	6.54	Ki	290	nM	CHEMBL_ACT_8024636
CA1	6.48	Ki	328	nM	CHEMBL_ACT_12161327
CA1	6.48	Ki	328	nM	CHEMBL_ACT_12656011
CA1	6.48	Ki	328	nM	CHEMBL_ACT_13286753
CA1	6.48	Ki	328	nM	CHEMBL_ACT_14661429
CA1	6.48	Ki	328	nM	CHEMBL_ACT_15108382
CA1	6.48	Ki	328	nM	CHEMBL_ACT_15143328

Target pathways

Aggregated over 2 target gene(s): NAPEPLD, SLC12A3.

Top Reactome pathways

12 total, by targets touching each:

Pathway	Targets	Genes
Disease	2	NAPEPLD, SLC12A3
Retinoid cycle disease events	1	NAPEPLD
Biosynthesis of A2E, implicated in retinal degradation	1	NAPEPLD
Diseases associated with visual transduction	1	NAPEPLD
Transport of small molecules	1	SLC12A3
R-HSA-425393	1	SLC12A3
SLC-mediated transmembrane transport	1	SLC12A3
Cation-coupled Chloride cotransporters	1	SLC12A3
Defective SLC12A3 causes Gitelman syndrome (GS)	1	SLC12A3
SLC transporter disorders	1	SLC12A3
Disorders of transmembrane transporters	1	SLC12A3
Diseases of the neuronal system	1	NAPEPLD

Dominant GO biological processes

GO term	Targets
temperature homeostasis	1
phospholipid catabolic process	1
response to isolation stress	1
host-mediated modulation of intestinal microbiota composition	1
positive regulation of inflammatory response	1
N-acylethanolamine metabolic process	1
N-acylphosphatidylethanolamine metabolic process	1
positive regulation of brown fat cell differentiation	1
negative regulation of eating behavior	1
lipid metabolic process	1
phospholipid metabolic process	1
lipid catabolic process	1
monoatomic ion transport	1
sodium ion transport	1
cell volume homeostasis	1

Indications & clinical

Indications

26 indications (12 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
hypertensive disorder	4	MONDO:0005044	EFO:0000537
cardiovascular disorder	4	MONDO:0004995	EFO:0000319
chronic kidney disease	4	MONDO:0005300	EFO:0003884
congestive heart failure	4	MONDO:0005009	EFO:0000373
cirrhosis of liver	4	MONDO:0005155	EFO:0001422
nephrotic syndrome	4	MONDO:0005377	EFO:0004255
preeclampsia	4	MONDO:0005081	EFO:0000668
myocardial infarction	4	MONDO:0005068	EFO:0000612
glomerulonephritis	4	MONDO:0002462	MONDO:0002462
heart failure	4	MONDO:0005252	EFO:0003144
nephrolithiasis	3	MONDO:0008171	EFO:0004253
atherosclerosis	3	MONDO:0005311	EFO:0003914
coronary artery disorder	3	MONDO:0005010	EFO:0001645
autosomal dominant polycystic kidney disease	3	MONDO:0004691	EFO:1001496
essential hypertension	3	MONDO:0001134	MONDO:0001134
type 2 diabetes mellitus	3	MONDO:0005148	MONDO:0005148
kidney disorder	2	MONDO:0005240	EFO:0003086
diabetic kidney disease	2	MONDO:0005016	EFO:0000401
diabetes mellitus	1	MONDO:0005015	EFO:0000400
photosensitivity disease	1	MONDO:0006597	HP:0000992
metabolic syndrome X	0	MONDO:0011565	EFO:0000195

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

Clinical trials

Total trials: 237.

Phase distribution

Phase	Trials
PHASE4	85
PHASE3	53
Not specified	46
PHASE1	31
PHASE2	15
EARLY_PHASE1	4
PHASE2/PHASE3	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05917275	PHASE4	RECRUITING	Multi-Omics to Predict the Blood Pressure Response to Antihypertensives
NCT06041529	PHASE4	ACTIVE_NOT_RECRUITING	Study to Evaluate the Efficacy and Safety of TEL/AML/CTD in Elderly Patients With Essential Hypertension
NCT07593612	PHASE4	NOT_YET_RECRUITING	TACTIC-HF: Sequential Diuretic Strategies in Ambulatory Worsening Heart Failure
NCT00110422	PHASE4	COMPLETED	Irbesartan in the Treatment of Hypertensive Patients With Metabolic Syndrome
NCT00171054	PHASE4	COMPLETED	Efficacy and Safety of Valsartan Versus Amlodipine in Postmenopausal Women With Hypertension
NCT00171132	PHASE4	COMPLETED	VALENCE: Valsartan Versus Atenolol on Exercise Capacity in Hypertensive Overweight Postmenopausal Women
NCT00171561	PHASE4	COMPLETED	Valsartan/Hydrochlorothiazide Combination vs Amlodipine in Patients With Hypertension, Diabetes, and Albuminuria.
NCT00171782	PHASE4	COMPLETED	Hypertension and Cardiovascular Risk Factors
NCT00185068	PHASE4	COMPLETED	An Examination of the Safety and Blood Pressure Lowering Effect of Increasing Doses of Benicar® and Benicar® HCT in Patients With Hypertension
NCT00224549	PHASE4	COMPLETED	PHARES Study: Management of Resistant Hypertension
NCT00234858	PHASE4	COMPLETED	Tarka vs. Hyzaar in Patients With Metabolic Syndrome (STAR)
NCT00246519	PHASE4	COMPLETED	Pharmacogenomic Evaluation of Antihypertensive Responses
NCT00263393	PHASE4	COMPLETED	Rural Andhra Pradesh Cardiovascular Prevention Study (RAPCAPS)
NCT00274638	PHASE4	COMPLETED	PROBE Parallel 6-week Treatment Comparing Telmisartan/Hydrochlorothiazide (HCT) (40/12.5 or 80/12.5) With Losartan/HCT (50/12.5) Using Ambulatory Blood Pressure Monitoring (ABPM)
NCT00277472	PHASE4	COMPLETED	Efficacy and Safety of Valsartan/Hydrochlorothiazide Combination Therapy in Patients With Hypertension
NCT00280540	PHASE4	COMPLETED	Efficacy and Safety of Valsartan/Hydrochlorothiazide Combination Therapy in Patients With Hypertension
NCT00306696	PHASE4	COMPLETED	Examining the Effect of Different Diuretics on Fluid Retention in Diabetics Treated With Rosiglitazone.
NCT00369538	PHASE4	SUSPENDED	Specific Blockage of Angiotensine 2 and Podocyturia in Glomerular Nephropathies With Hypertension and Proteinuria
NCT00412932	PHASE4	COMPLETED	An Examination of the Blood Pressure Lowering Ability and Safety of Olmesartan Medoxomil in Elderly Patients With Hypertension
NCT00443612	PHASE4	COMPLETED	Irbesartan/Hydrochlorothiazide National Taiwan University Hospital Listing
NCT00457483	PHASE4	COMPLETED	Nijmegen Antihypertensive Management Improvement Study
NCT00492128	PHASE4	COMPLETED	Kanagawa Combination Anti-hypertensive Therapy (K-CAT)
NCT00500604	PHASE4	COMPLETED	Efficacy of Irbesartan/Hydrochlorothiazide Versus Valsartan/Hydrochlorothiazide in Mild to Moderate Hypertension
NCT00535925	PHASE4	COMPLETED	Nephropathy In Type 2 Diabetes and Cardio-renal Events
NCT00605202	PHASE4	COMPLETED	Effect of Licorice and Hydrochlorothiazide on Plasma Potassium
NCT00607035	PHASE4	COMPLETED	The Japan-Combined Treatment With Olmesartan and a Calcium Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy Study (J-CORE)
NCT00621153	PHASE4	COMPLETED	Candesartan Effect in Second Stage Arterial Hypertension
NCT00654745	PHASE4	COMPLETED	18 Week Study Evaluating Safety and Efficacy of Olmesartan, Amlodipine, and Hydrochlorothiazide, in Type 2 Diabetics
NCT00661895	PHASE4	COMPLETED	Black Education and Treatment of Hypertension (BEAT HTN)
NCT00670566	PHASE4	COMPLETED	Irbesartan/Hydrochlorothiazide to Control Elevated Blood Pressure to Target in Moderate to Severe Hypertensive Patients
NCT00745953	PHASE4	WITHDRAWN	Regression of Fatty Heart by Valsartan Therapy
NCT00760266	PHASE4	COMPLETED	Blood Pressure Lowering of Aliskiren HCTZ Compared to HCTZ in Stage 2 Systolic Hypertension in Older Population
NCT00765947	PHASE4	COMPLETED	Efficacy and Tolerability of an Aliskiren-based Treatment Algorithm in Patients With Mild to Moderate Hypertension
NCT00772499	PHASE4	COMPLETED	Vascular Improvement With Olmesartan Medoxomil Study
NCT00772577	PHASE4	COMPLETED	Study of the Efficacy and Safety of Aliskiren HCTZ vs Ramipril in Obese Patients (BMI ≥ 30) With Stage 2 Hypertension
NCT00775814	PHASE4	COMPLETED	Efficacy of Candesartan on Reducing Blood Pressure in Insulin-Resistant, Obese Patients With Hypertension.
NCT00787605	PHASE4	COMPLETED	Aliskiren HCTZ Compared to Amlodipine in Patients With Stage 2 Systolic Hypertension and Diabetes Mellitus
NCT00791258	PHASE4	COMPLETED	A Dose Escalation Study of a Combination Antihypertensive Drug in the Treatment of Various Groups of Patients Who do Not Respond to Single Drug Treatment of Their High Blood Pressure
NCT00797316	PHASE4	COMPLETED	Aliskiren Plus HCTZ Compared to Aliskiren in Metabolic Syndrome Patients With Stage 2 Systolic Hypertension
NCT00821574	PHASE4	COMPLETED	Reducing the Overall Risk Level in Patients Suffering From Metabolic Syndrome

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 50 clinical and 123 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.

2 molecules share ≥1 primary target. Top 2 by shared-target count:

Molecule	Source	Status	Shared targets
HEXACHLOROPHENE	ChEMBL	Phase 4 (approved)	NAPEPLD
Orlistat	PubChem	Approved	NAPEPLD