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Identification
NameBenzthiazide
Accession NumberDB00562  (APRD00728)
Typesmall molecule
Groupsapproved
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
3-((Benzylthio)methyl)-6-chloro-7-sulfamoyl-2H-benzo-1,2,4-thiadiazine 1,1-dioxideNot AvailableNot Available
3-Benzylthiomethyl-6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxideNot AvailableNot Available
3-Benzylthiomethyl-6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxideNot AvailableNot Available
6-chloro-1,1-dioxo-3-(Phenylmethylsulfanylmethyl)-4H-benzo[e][1,2,4]thiadiazine-7-sulfonamideNot AvailableNot Available
6-chloro-7-Sulfamoyl-3-benzylthiomethyl-2H-1,2,4-benzothiadiazine 1,1-dioxideNot AvailableNot Available
BenzothiazideFrenchINN
BenzotiazidaSpanishINN
BenzthiazidGermanINN
BenzthiazideNot AvailableNot Available
BenzthiazidumLatinINN
BenztiazideNot AvailableDCIT
SaltsNot Available
Brand names
NameCompany
AquatagNot Available
DihydrexNot Available
DiucenNot Available
EdemaxNot Available
ExnaNot Available
FovenNot Available
Brand mixtures
Brand NameIngredients
Dyrenium compositumBenzthiazide + Triamterene
DytideBenzthiazide + Triamterene
Categories
CAS number91-33-8
WeightAverage: 431.937
Monoisotopic: 430.983495728
Chemical FormulaC15H14ClN3O4S3
InChI KeyNDTSRXAMMQDVSW-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-1$l^{6},2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=C(Cl)C=C2NC(CSCC3=CC=CC=C3)=NS(=O)(=O)C2=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassThiadiazines
SubclassBenzothiadiazines
Direct parentBenzothiadiazines
Alternative parentsBenzenesulfonamides; Chlorobenzenes; Aryl Chlorides; Sulfonyls; Sulfonamides; Polyamines; Thioethers; Organochlorides
Substituentschlorobenzene; benzene; aryl halide; aryl chloride; sulfonamide; sulfonic acid derivative; sulfonyl; thioether; polyamine; organohalogen; organochloride; organonitrogen compound
Classification descriptionThis compound belongs to the benzothiadiazines. These are organic compounds containing a benzene fused to a thiadiazine ring (a six-member ring with two nitrogen atoms and a sulfur atom).
Pharmacology
IndicationFor the treatment of high blood pressure and management of edema.
PharmacodynamicsBenzthiazide 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 actionAs 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.
AbsorptionAbsorbed in the digestive tract.
Volume of distributionNot Available
Protein binding30%
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicitySymptoms of overdose include nausea, vomiting, fatigue, urinary problems and drowsiness.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9593
Blood Brain Barrier - 0.8349
Caco-2 permeable - 0.705
P-glycoprotein substrate Substrate 0.5849
P-glycoprotein inhibitor I Non-inhibitor 0.7928
P-glycoprotein inhibitor II Non-inhibitor 0.5851
Renal organic cation transporter Non-inhibitor 0.6761
CYP450 2C9 substrate Non-substrate 0.7261
CYP450 2D6 substrate Non-substrate 0.8285
CYP450 3A4 substrate Non-substrate 0.557
CYP450 1A2 substrate Non-inhibitor 0.9046
CYP450 2C9 substrate Inhibitor 0.7652
CYP450 2D6 substrate Non-inhibitor 0.8733
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Inhibitor 0.7959
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.681
Ames test Non AMES toxic 0.8436
Carcinogenicity Non-carcinogens 0.7729
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 1.6663 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9085
hERG inhibition (predictor II) Non-inhibitor 0.879
Pharmacoeconomics
Manufacturers
  • Solvay pharmaceuticals
  • Private formulations inc
  • Ah robins inc
  • Pfizer laboratories div pfizer inc
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point210-211McLamore, 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 solubility1.29e-02 g/lALOGPS
logP2.26ALOGPS
logP1.84ChemAxon
logS-4.5ALOGPS
pKa (strongest acidic)8.77ChemAxon
pKa (strongest basic)1.25ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count6ChemAxon
hydrogen donor count2ChemAxon
polar surface area118.69ChemAxon
rotatable bond count5ChemAxon
refractivity104.14ChemAxon
polarizability41.5ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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 ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00651
KEGG CompoundC07759
PubChem Compound2343
PubChem Substance46506752
ChemSpider2253
ChEBI3047
ChEMBLCHEMBL1201039
Therapeutic Targets DatabaseDAP000603
PharmGKBPA164776841
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
DigoxinPossible electrolyte variations and arrhythmias
LithiumThe thiazide diuretic, benzthiazide, may increase serum levels of lithium.
Food InteractionsNot Available

Targets

1. Solute carrier family 12 member 3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 12 member 3 P55017 Details

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. Pubmed
  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. Pubmed

2. Carbonic anhydrase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 1 P00915 Details

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. Pubmed
  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. Pubmed

3. Carbonic anhydrase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 2 P00918 Details

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. Pubmed
  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. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

4. Carbonic anhydrase 4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 4 P22748 Details

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. Pubmed
  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. Pubmed

5. Carbonic anhydrase 9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 9 Q16790 Details

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. Epub 2008 Dec 24. Pubmed

6. Carbonic anhydrase 12

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 12 O43570 Details

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. Epub 2008 Dec 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11