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Identification
Name Trichlormethiazide
Accession Number DB01021 (APRD00031)
Type small molecule
Groups approved
Description

A thiazide diuretic with properties similar to those of hydrochlorothiazide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p830)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Achletin
  • Anatran
  • Anistadin
  • Aponorin
  • Carvacron
  • Chlopolidine
  • Cretonin
  • Diu-Hydrin
  • Diurazida
  • Diurese
  • Diuroral
  • Esmarin
  • Eurinol
  • Fluitran
  • Flurese
  • Flutra
  • Gangesol
  • Hydrotrichlorothiazide
  • Intromene
  • Isestran
  • Kubacron
  • Metahydrin
  • Metatensin
  • Nakva
  • Naqua
  • Naquasone
  • Salurin
  • Schebitran
  • Tachionin
  • Tolcasone
  • Trichlorex
  • Trichlormas
  • Trichlormetazid
  • Trichlormethiazid
  • Trichlormethiazide W/ Reserpine
  • Trichloromethiadiazide
  • Trichloromethiazide
  • Triclordiuride
  • Triclormetiazide
  • Triflumen
Brand name mixtures Not Available
Categories
  • Antihypertensive Agents
  • Diuretics
  • Sodium Chloride Symporter Inhibitors
CAS number 133-67-5
Weight Average: 380.656
Monoisotopic: 378.902180260
Chemical Formula C8H8Cl3N3O4S2
InChI Key InChIKey=LMJSLTNSBFUCMU-UHFFFAOYSA-N
InChI
InChI=1S/C8H8Cl3N3O4S2/c9-3-1-4-6(2-5(3)19(12,15)16)20(17,18)14-8(13-4)7(10)11/h1-2,7-8,13-14H,(H2,12,15,16)
Plain Text
IUPAC Name
6-chloro-3-(dichloromethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=CC2=C(NC(NS2(=O)=O)C(Cl)Cl)C=C1Cl
Plain Text
Mass Spec show (8.1 KB)
Taxonomy
Kingdom Organic
Classes
  • Benzenesulfonamides
  • Sulfanilamides
Substructures
  • Sulfonyls
  • Benzene and Derivatives
  • Aryl Halides
  • Benzenesulfonamides
  • Halobenzenes
  • Aminals and Derivatives
  • Alkyl Halides
  • Heterocyclic compounds
  • Aromatic compounds
  • Thiadiazines
  • Sulfanilamides
  • Sulfonamides
  • Anilines
Pharmacology
Indication Used in the treatment of oedema (including that associated with heart failure) and hypertension.
Pharmacodynamics Trichloromethiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Trichloromethiazide has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomer-ulonephritis, and chronic renal failure. Trichloromethiazide is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. Like other thiazides, Trichloromethiazide 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 Trichlormethiazide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. As a diuretic, Trichloromethiazide 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 Trichloromethiazide 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 Trichloromethiazide 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.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Oral Rat LD50 = 5600 mg/kg, oral Mouse LD50 = 2600 mg/kg
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00121 Trichlormethiazide Pathway SMP00121
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Schering corp sub schering plough corp
  • Lannett co inc
  • Mm mast and co
  • Impax laboratories inc
  • Par pharmaceutical inc
  • Sandoz inc
  • Tg united labs llc
  • Watson laboratories inc
Packagers
Dosage forms Not Available
Prices
Unit description Cost Unit
Trichlormethiazide powder 15.0 USD g
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility 0.8 mg/mL at 25 oC [MERCK (1989)] PhysProp
logP 0.7 PhysProp
logS -2.68 [ADME Research, USCD] PhysProp
pKa 8.6 Various sources
Predicted Properties
Property Value Source
water solubility 4.15e-01 g/l ALOGPS
logP 0.86 ALOGPS
logP 0.97 ChemAxon Molconvert
logS -2.96 ALOGPS
pKa 9.80 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 118.36 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 77.44 ChemAxon Molconvert
polarizability 31.97 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00658 Link_out
KEGG Compound C07767 Link_out
PubChem Compound 5560 Link_out
PubChem Substance 46508880 Link_out
ChemSpider 5359 Link_out
BindingDB 26998 Link_out
Therapeutic Targets Database DAP000035 Link_out
PharmGKB PA451754 Link_out
Drug Product Database 0 Link_out
ATC Codes
  • C03AA06
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (73.2 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Solute carrier family 12 member 1

Pharmacological action: yes
Actions: inhibitor

Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume

Organism class: human
UniProt ID: Q13621 Link_out
Gene: SLC12A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Li J, Wang DH: Function and regulation of epithelial sodium transporters in the kidney of a salt-sensitive hypertensive rat model. J Hypertens. 2007 May;25(5):1065-72. Pubmed
  2. Hasannejad H, Takeda M, Taki K, Shin HJ, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onozato ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H: Interactions of human organic anion transporters with diuretics. J Pharmacol Exp Ther. 2004 Mar;308(3):1021-9. Epub 2003 Nov 10. Pubmed
  3. Smith SM: Thiazide diuretics. N Engl J Med. 2010 Feb 18;362(7):659-60; author reply 660. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Sodium/potassium-transporting ATPase alpha-1 chain

Pharmacological action: yes
Actions: inhibitor

This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients

Organism class: human
UniProt ID: P05023 Link_out
Gene: ATP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Takahashi N, Kondo Y, Fujiwara I, Ito O, Igarashi Y, Abe K: Characterization of Na+ transport across the cell membranes of the ascending thin limb of Henle’s loop. Kidney Int. 1995 Mar;47(3):789-94. Pubmed

3. Carbonic anhydrase 1

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: P00915 Link_out
Gene: CA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. 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

4. Carbonic anhydrase 2

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: P00918 Link_out
Gene: CA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. 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

5. Carbonic anhydrase 4

Pharmacological action: unknown
Actions: inhibitor

Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4

Organism class: human
UniProt ID: P22748 Link_out
Gene: CA4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. 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
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:45

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.