Metolazone

Summary

Metolazone (CHEMBL878) is an approved small-molecule diuretic (ATC C03BA08) targeting SLC12A3; indicated across 6 conditions including cardiovascular disorder and heart failure.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: C03BA08
• Targets: 1 (SLC12A3)
• Indications: 6 conditions
• Clinical trials: 22
• Chemistry: 365.8 Da · C16H16ClN3O3S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL878
Name	Metolazone
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	4170
ChEBI	CHEBI:64354
ATC	C03BA08
Molecular formula	C16H16ClN3O3S
Molecular weight	365.8
InChIKey	AQCHWTWZEMGIFD-UHFFFAOYSA-N

SMILES: CC1NC2=CC(=C(C=C2C(=O)N1C3=CC=CC=C3C)S(=O)(=O)N)Cl

IUPAC name: 7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2-dihydroquinazoline-6-sulfonamide

ChEBI definition: A quinazoline that consists of 1,2,3,4-tetrahydroquinazolin-4-one bearing additional methyl, 2-tolyl, sulfamyl and chloro substituents at positions 2, 3, 6 and 7 respectively. A quinazoline diuretic, with properties similar to thiazide diuretics.

Pharmacological roles (ChEBI): diuretic, antihypertensive agent, ion transport inhibitor.

Also known as: Diulo, Metazoline, Metenix, Metolazona, Metolazone, Metozalone, Mykrox, Normelan, NSC-759581, Oldren, Xuret, Zaroxolyn

Patent coverage: 3,461 distinct patent families (13,165 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 13,158 (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
SLC12A3	Na-Cl symporter	Inhibition		0.2%	P55017

Broader ChEMBL bioactivity targets: 11 (assay-derived). Sample: Lysine-specific demethylase 4E, Ferritin light chain, 15-hydroxyprostaglandin dehydrogenase [NAD(+)], Endonuclease 4, Peripheral myelin protein 22, Carbonic anhydrase 2, Carbonic anhydrase 7, Nuclear factor NF-kappa-B p105 subunit, Cytochrome P450 3A4, Aldehyde dehydrogenase 1A1, 3-hydroxyacyl-CoA dehydrogenase type-2.

Bioactivity

ChEMBL activities: 4 potent at pChembl ≥ 5 of 21 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
CA7	8.68	Ki	2.1	nM	CHEMBL_ACT_13859514
CA2	5.7	Ki	2000	nM	CHEMBL_ACT_26047522
CA2	5.55	Kd	2800	nM	CHEMBL_ACT_26047531
HPGD	5.05	Potency	8912	nM	CHEMBL_ACT_4768762

Target pathways

Aggregated over 1 target gene(s): SLC12A3.

Top Reactome pathways

8 total, by targets touching each:

Pathway	Targets	Genes
Disease	1	SLC12A3
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

Dominant GO biological processes

GO term	Targets
monoatomic ion transport	1
sodium ion transport	1
cell volume homeostasis	1
sodium ion transmembrane transport	1
chloride ion homeostasis	1
potassium ion homeostasis	1
sodium ion homeostasis	1
renal sodium ion absorption	1
response to salt	1
chloride transmembrane transport	1
response to aldosterone	1
potassium ion import across plasma membrane	1
transmembrane transport	1

Indications & clinical

Indications

5 approved indications. FDA phase 4, plus an anticancer drug’s labelled cancer uses (which ChEMBL often logs at phase 3).

Indication	Phase	MONDO	EFO
cardiovascular disorder	4	MONDO:0004995	EFO:0000319
heart failure	4	MONDO:0005252	EFO:0003144
congestive heart failure	4	MONDO:0005009	EFO:0000373
hypertensive disorder	4	MONDO:0005044	EFO:0000537
preeclampsia	4	MONDO:0005081	EFO:0000668

1 disease in clinical trials (phase 1–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)	Phase	MONDO	EFO
chronic kidney disease	2	MONDO:0005300	EFO:0003884

Clinical trials

Total trials: 22.

Phase distribution

Phase	Trials
PHASE4	6
PHASE2	5
Not specified	5
PHASE3	3
PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06166654	PHASE4	RECRUITING	Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload
NCT06414759	PHASE4	RECRUITING	Efficacy and Safety of Combination Diuretic Therapy in Patients With Acute Decompensated Heart Failure and Volume Overload
NCT02606253	PHASE4	COMPLETED	Comparison of Oral or Intravenous Thiazides vs Tolvaptan in Diuretic Resistant Decompensated Heart Failure
NCT03574857	PHASE4	TERMINATED	Prospective Comparison of Metolazone Versus Chlorothiazide for Acute Decompensated Heart Failure With Diuretic Resistance
NCT03746002	PHASE4	TERMINATED	Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing
NCT05986773	PHASE4	TERMINATED	Diuretic Strategies in Acute Heart Failure Patients at High Risk for Diuretic Resistance
NCT02620384	PHASE3	TERMINATED	Metolazone As Early Add On Therapy For Acute Decompensated Heart Failure (MELT-HF)–A Single Center Pilot Study.
NCT04163588	PHASE3	UNKNOWN	Sequential Nephron Blockade in Acute Heart Failure
NCT04860011	PHASE3	UNKNOWN	DAPAgliflozin Versus Thiazide Diuretic in Patients With Heart Failure and Diuretic RESISTance
NCT04438213	PHASE2	RECRUITING	Ertugliflozin in Chronic Heart Failure
NCT07372040	PHASE2	RECRUITING	Add-on Diuretics in Acute Decompensated Heart Failure
NCT04542304	PHASE2	TERMINATED	Efficacy of Diuretics in Kidney Disease
NCT05633758	PHASE2	WITHDRAWN	Metolazone As Early Add On Therapy For Acute Decompensated Heart Failure
NCT06326112	PHASE2	UNKNOWN	Role of Active Deresuscitation After Resuscitation:
NCT00649051	PHASE1	COMPLETED	Fasting Study of Metolazone Tablets 2.5 mg and Zaroloxyn® Tablets 2.5 mg
NCT00649181	PHASE1	COMPLETED	Fasting Study of Metolazone Tablets 5 mg and Zaroloxyn® Tablets 5 mg
NCT00650195	PHASE1	COMPLETED	Fasting Study of Metolazone Tablets 10 mg and Zaroloxyn® Tablets 10 mg
NCT06273397	Not specified	NOT_YET_RECRUITING	Acetazolamide or Metolazone in Acute Heart Failure
NCT07199088	Not specified	RECRUITING	Comparative Efficacy and Safety of Acetazolamide Versus Metolazone as an Adjunct to Standard Therapy in Patients With Acute Decompensated Heart Failure
NCT00690521	Not specified	COMPLETED	A Comparison of Hydrochlorothiazide and Metolazone in Combination With Furosemide in Congestive Heart Failure Patients
NCT01817803	Not specified	WITHDRAWN	A Prospective, Single-center, Open-label, Pilot Study to Compare the Effectiveness and Safety of Diuretics Add-On Strategy in Chronic Heart Failure Patients (DIOS 1)
NCT02047422	Not specified	WITHDRAWN	A Prospective, Single-center, Randomized, Controlled, Open-label, Pilot Study to Compare the Effectiveness and Safety of DIuretics Add-On Strategy in Acute Decompensated Heart Failure Patients (DIOS II)

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Related molecules

Related molecules

No competitor molecules sharing a primary target (ChEMBL phase ≥2 or PubChem drug-class).