Benzthiazide

Identification

Generic Name
Benzthiazide
DrugBank Accession Number
DB00562
Background

Benzthiazide is used to treat hypertension and edema. Like other thiazides, benzthiazide promotes water loss from the body (diuretics). They inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 431.937
Monoisotopic: 430.983495728
Chemical Formula
C15H14ClN3O4S3
Synonyms
  • 3-((benzylthio)methyl)-6-chloro-7-sulfamoyl-2H-benzo-1,2,4-thiadiazine 1,1-dioxide
  • 3-benzylthiomethyl-6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
  • 3-benzylthiomethyl-6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide
  • 6-chloro-1,1-dioxo-3-(phenylmethylsulfanylmethyl)-4H-benzo[e][1,2,4]thiadiazine-7-sulfonamide
  • 6-chloro-7-sulfamoyl-3-benzylthiomethyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
  • Benzothiazide
  • Benzotiazida
  • Benzthiazid
  • Benzthiazide
  • Benzthiazidum
  • Benztiazide
External IDs
  • P 1393

Pharmacology

Indication

For the treatment of high blood pressure and management of edema.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Benzthiazide is used to treat hypertension and edema. Like other thiazides, benzthiazide promotes water loss from the body (diuretics). They inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.

Mechanism of action

As a diuretic, benzthiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like benzthiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of benzthiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

TargetActionsOrganism
ASolute carrier family 12 member 3
inhibitor
Humans
ACarbonic anhydrase
inhibitor
Humans
UCarbonic anhydrase 1
inhibitor
Humans
UCarbonic anhydrase 2
inhibitor
Humans
UCarbonic anhydrase 4
inhibitor
Humans
UCarbonic anhydrase 9
inhibitor
Humans
UCarbonic anhydrase 12
inhibitor
Humans
Absorption

Absorbed in the digestive tract.

Volume of distribution

Not Available

Protein binding

30%

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Symptoms of overdose include nausea, vomiting, fatigue, urinary problems and drowsiness.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirBenzthiazide may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
AbciximabThe therapeutic efficacy of Abciximab can be decreased when used in combination with Benzthiazide.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Benzthiazide.
AcebutololThe therapeutic efficacy of Acebutolol can be increased when used in combination with Benzthiazide.
AceclofenacThe therapeutic efficacy of Benzthiazide can be decreased when used in combination with Aceclofenac.
Food Interactions
Not Available

Products

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International/Other Brands
Aquatag / Dihydrex / Diucen / Edemax / Exna / Foven

Categories

ATC Codes
G01AE10 — Combinations of sulfonamides
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1,2,4-benzothiadiazine-1,1-dioxides. These are aromatic heterocyclic compounds containing a 1,2,4-benzothiadiazine ring system with two S=O bonds at the 1-position.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Thiadiazines
Sub Class
Benzothiadiazines
Direct Parent
1,2,4-benzothiadiazine-1,1-dioxides
Alternative Parents
Organosulfonamides / Imidolactams / Benzene and substituted derivatives / Aryl chlorides / Aminosulfonyl compounds / Sulfenyl compounds / Dialkylthioethers / Azacyclic compounds / Amidines / Organopnictogen compounds
show 3 more
Substituents
1,2,4-benzothiadiazine-1,1-dioxide / Amidine / Aminosulfonyl compound / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Dialkylthioether / Hydrocarbon derivative
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
sulfonamide, benzothiadiazine (CHEBI:3047)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1TD8J48L61
CAS number
91-33-8
InChI Key
NDTSRXAMMQDVSW-UHFFFAOYSA-N
InChI
InChI=1S/C15H14ClN3O4S3/c16-11-6-12-14(7-13(11)25(17,20)21)26(22,23)19-15(18-12)9-24-8-10-4-2-1-3-5-10/h1-7H,8-9H2,(H,18,19)(H2,17,20,21)
IUPAC Name
3-[(benzylsulfanyl)methyl]-6-chloro-1,1-dioxo-4H-1lambda6,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=CC2=C(C=C1Cl)N=C(CSCC1=CC=CC=C1)NS2(=O)=O

References

Synthesis Reference

Samuel M. Fainberg, Porfirio F. Perez, "Stable solution of benzthiazide (3-[benzythiol methyl]-6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide) suitable for parenteral administration and process of preparation." U.S. Patent US4022894, issued May 10, 1977.

US4022894
General References
Not Available
Human Metabolome Database
HMDB0014702
KEGG Drug
D00651
KEGG Compound
C07759
PubChem Compound
2343
PubChem Substance
46506752
ChemSpider
2253
BindingDB
50238676
RxNav
19008
ChEBI
3047
ChEMBL
CHEMBL1201039
ZINC
ZINC000003871698
Therapeutic Targets Database
DAP000603
PharmGKB
PA164776841
Wikipedia
Benzthiazide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
  • Solvay pharmaceuticals
  • Private formulations inc
  • Ah robins inc
  • Pfizer laboratories div pfizer inc
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)210-211McLamore, W.M. and Laubach, G.D.; U.S. Patent 3,111,517; November 19, 1963; assigned to Chas. Pfizer & Co., Inc.
water solubility8.91 mg/LNot Available
logP1.73BERTHOD,A ET AL. (1999)
pKa6BERTHOD,A ET AL. (1999)
Predicted Properties
PropertyValueSource
Water Solubility0.0121 mg/mLALOGPS
logP2.25ALOGPS
logP1.84Chemaxon
logS-4.6ALOGPS
pKa (Strongest Acidic)9.18Chemaxon
pKa (Strongest Basic)-4.7Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area118.69 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity104.14 m3·mol-1Chemaxon
Polarizability41.5 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9593
Blood Brain Barrier-0.8349
Caco-2 permeable-0.705
P-glycoprotein substrateSubstrate0.5849
P-glycoprotein inhibitor INon-inhibitor0.7928
P-glycoprotein inhibitor IINon-inhibitor0.5851
Renal organic cation transporterNon-inhibitor0.6761
CYP450 2C9 substrateNon-substrate0.7261
CYP450 2D6 substrateNon-substrate0.8285
CYP450 3A4 substrateNon-substrate0.557
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorInhibitor0.7652
CYP450 2D6 inhibitorNon-inhibitor0.8733
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.681
Ames testNon AMES toxic0.8436
CarcinogenicityNon-carcinogens0.7729
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.6663 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9085
hERG inhibition (predictor II)Non-inhibitor0.879
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0006-9242000000-15561d025e3aa0c75308
Mass Spectrum (Electron Ionization)MSsplash10-06r6-9624000000-532194fb14045a87f8de
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0000900000-5c93555b6a62b5e7d7c3
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a59-2008900000-b414e028331ad570d42c
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0001900000-7fb86847d2c464ca2067
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0009000000-207dbd7efebf7ff87b1d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-014l-9010000000-92d10fe457d8f719c2dc
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-9006000000-3125ecd2610fa906c328
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-201.4652935
predicted
DarkChem Lite v0.1.0
[M-H]-186.41191
predicted
DeepCCS 1.0 (2019)
[M+H]+202.3666935
predicted
DarkChem Lite v0.1.0
[M+H]+188.76993
predicted
DeepCCS 1.0 (2019)
[M+Na]+202.0038935
predicted
DarkChem Lite v0.1.0
[M+Na]+195.08519
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Key mediator of sodium and chloride reabsorption in this nephron segment, accounting for a significant fraction of renal sodium reabsorption.
Gene Name
SLC12A3
Uniprot ID
P55017
Uniprot Name
Solute carrier family 12 member 3
Molecular Weight
113138.04 Da
References
  1. Blanchard A, Vallet M, Dubourg L, Hureaux M, Allard J, Haymann JP, de la Faille R, Arnoux A, Dinut A, Bergerot D, Becker PH, Courand PY, Baron S, Houillier P, Tack I, Devuyst O, Jeunemaitre X, Azizi M, Vargas-Poussou R: Resistance to Insulin in Patients with Gitelman Syndrome and a Subtle Intermediate Phenotype in Heterozygous Carriers: A Cross-Sectional Study. J Am Soc Nephrol. 2019 Aug;30(8):1534-1545. doi: 10.1681/ASN.2019010031. Epub 2019 Jul 8. [Article]
  2. Ellison DH: The thiazide-sensitive na-cl cotransporter and human disease: reemergence of an old player. J Am Soc Nephrol. 2003 Feb;14(2):538-40. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.

Components:
References
  1. LEIBMAN KC, ALFORD D, BOUDET RA: Nature of the inhibition of carbonic anhydrase by acetazolamide and benzthiazide. J Pharmacol Exp Ther. 1961 Mar;131:271-4. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.
Gene Name
CA1
Uniprot ID
P00915
Uniprot Name
Carbonic anhydrase 1
Molecular Weight
28870.0 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion in...
Gene Name
CA2
Uniprot ID
P00918
Uniprot Name
Carbonic anhydrase 2
Molecular Weight
29245.895 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina an...
Gene Name
CA4
Uniprot ID
P22748
Uniprot Name
Carbonic anhydrase 4
Molecular Weight
35032.075 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide. Participates in pH regulation. May be involved in the control of cell proliferation and transformation. Appears to be a novel specific biomarker for a cervic...
Gene Name
CA9
Uniprot ID
Q16790
Uniprot Name
Carbonic anhydrase 9
Molecular Weight
49697.36 Da
References
  1. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide.
Gene Name
CA12
Uniprot ID
O43570
Uniprot Name
Carbonic anhydrase 12
Molecular Weight
39450.615 Da
References
  1. Temperini C, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference. Bioorg Med Chem. 2009 Feb 1;17(3):1214-21. doi: 10.1016/j.bmc.2008.12.023. Epub 2008 Dec 24. [Article]

Drug created at June 13, 2005 13:24 / Updated at December 02, 2023 06:52