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Identification
NameCyclothiazide
Accession NumberDB00606  (APRD00895, EXPT01082)
TypeSmall Molecule
GroupsApproved
Description

As a diuretic, cyclothiazide 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 cyclothiazide 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 cyclothiazide 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. Cyclothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It 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.

Structure
Thumb
Synonyms
6-chloro-3-(2-Norbornen-5-yl)-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide
6-chloro-3,4-dihydro-3-(2-Norbornen-5-yl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
6-chloro-3,4-dihydro-3-(2-Norbornen-5-yl)-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide
6-chloro-3,4-dihydro-3-(5-Norbornen-2-yl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
Ciclotiazida
Ciclotiazide
Cyclothiazide
Cyclothiazidum
External Identifiers Not Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
AcquirelNot Available
AnhydronLilly
DoburilBoehringer Ingelheim
FluidilNot Available
RenazideNot Available
TensodiuralNot Available
ValmiranBoehringer Ingelheim
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIP71U09G5BW
CAS number2259-96-3
WeightAverage: 389.878
Monoisotopic: 389.027075102
Chemical FormulaC14H16ClN3O4S2
InChI KeyInChIKey=BOCUKUHCLICSIY-UHFFFAOYSA-N
InChI
InChI=1S/C14H16ClN3O4S2/c15-10-5-11-13(6-12(10)23(16,19)20)24(21,22)18-14(17-11)9-4-7-1-2-8(9)3-7/h1-2,5-9,14,17-18H,3-4H2,(H2,16,19,20)
IUPAC Name
3-{bicyclo[2.2.1]hept-5-en-2-yl}-6-chloro-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide
SMILES
NS(=O)(=O)C1=C(Cl)C=C2NC(NS(=O)(=O)C2=C1)C1CC2CC1C=C2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 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).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassThiadiazines
Sub ClassBenzothiadiazines
Direct ParentBenzothiadiazines
Alternative Parents
Substituents
  • Benzothiadiazine
  • Secondary aliphatic/aromatic amine
  • Benzenoid
  • Aryl halide
  • Aryl chloride
  • Aminosulfonyl compound
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Azacycle
  • Secondary amine
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationCyclothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It 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.
PharmacodynamicsLike other thiazides, cyclothiazide promotes water loss from the body (diuretics). It inhibits 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. Cyclothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy. Cyclothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.
Mechanism of actionHydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.Hydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityOral LD50 in mouse is > 10000 mg/kg, and > 4000 mg/kg in rat. Signs of overdose include those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered hypokalemia may accentuate cardiac arrhythmias.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9936
Blood Brain Barrier-0.8102
Caco-2 permeable-0.7087
P-glycoprotein substrateNon-substrate0.6003
P-glycoprotein inhibitor INon-inhibitor0.8315
P-glycoprotein inhibitor IINon-inhibitor0.9504
Renal organic cation transporterNon-inhibitor0.894
CYP450 2C9 substrateNon-substrate0.6644
CYP450 2D6 substrateNon-substrate0.8212
CYP450 3A4 substrateNon-substrate0.6385
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorInhibitor0.7478
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8682
Ames testNon AMES toxic0.8015
CarcinogenicityNon-carcinogens0.813
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.9232 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9813
hERG inhibition (predictor II)Non-inhibitor0.8693
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
  • Pharmacia and upjohn co
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point229-230Muller, E. and Hasspacher, K.; US. Patent 3,275,625; September 27,1966; assigned to Boehringer lngelheim GmbH, Germany.
logP1.95YAMAZAKI,M ET AL. (1984)
Predicted Properties
PropertyValueSource
Water Solubility0.279 mg/mLALOGPS
logP1.32ALOGPS
logP0.94ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)9.06ChemAxon
pKa (Strongest Basic)-2.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area118.36 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity92.65 m3·mol-1ChemAxon
Polarizability37.1 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (9.61 KB)
SpectraNot Available
References
Synthesis Reference

Muller, E. and Hasspacher, K.; US. Patent 3,275,625; September 27,1966; assigned to
Boehringer lngelheim GmbH, Germany.

General ReferencesNot Available
External Links
ATC CodesC03AA09
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSDownload (74.8 KB)
Interactions
Drug Interactions
Drug
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Cyclothiazide.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Cyclothiazide.
BuprenorphineThe risk or severity of adverse effects can be increased when Buprenorphine is combined with Cyclothiazide.
ButorphanolThe risk or severity of adverse effects can be increased when Butorphanol is combined with Cyclothiazide.
CaffeineThe risk or severity of adverse effects can be increased when Caffeine is combined with Cyclothiazide.
ChlorphenamineThe risk or severity of adverse effects can be increased when Chlorphenamine is combined with Cyclothiazide.
CodeineThe risk or severity of adverse effects can be increased when Codeine is combined with Cyclothiazide.
DihydrocodeineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Cyclothiazide.
FentanylThe risk or severity of adverse effects can be increased when Fentanyl is combined with Cyclothiazide.
HydrocodoneThe risk or severity of adverse effects can be increased when Hydrocodone is combined with Cyclothiazide.
HydromorphoneThe risk or severity of adverse effects can be increased when Hydromorphone is combined with Cyclothiazide.
LevorphanolThe risk or severity of adverse effects can be increased when Levorphanol is combined with Cyclothiazide.
MethadoneThe risk or severity of adverse effects can be increased when Methadone is combined with Cyclothiazide.
MorphineThe risk or severity of adverse effects can be increased when Morphine is combined with Cyclothiazide.
NalbuphineThe risk or severity of adverse effects can be increased when Nalbuphine is combined with Cyclothiazide.
OxycodoneThe risk or severity of adverse effects can be increased when Oxycodone is combined with Cyclothiazide.
OxymorphoneThe risk or severity of adverse effects can be increased when Oxymorphone is combined with Cyclothiazide.
PentazocineThe risk or severity of adverse effects can be increased when Pentazocine is combined with Cyclothiazide.
PethidineThe risk or severity of adverse effects can be increased when Pethidine is combined with Cyclothiazide.
RemifentanilThe risk or severity of adverse effects can be increased when Remifentanil is combined with Cyclothiazide.
SufentanilThe risk or severity of adverse effects can be increased when Sufentanil is combined with Cyclothiazide.
TapentadolThe risk or severity of adverse effects can be increased when Tapentadol is combined with Cyclothiazide.
TramadolThe risk or severity of adverse effects can be increased when Tramadol is combined with Cyclothiazide.
Food InteractionsNot Available

Targets

1. Sodium/potassium-transporting ATPase subunit gamma

Kind: Protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium/potassium-transporting ATPase subunit gamma P54710 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. Rammes G, Zeilhofer HU, Collingridge GL, Parsons CG, Swandulla D: Expression of early hippocampal CA1 LTP does not lead to changes in AMPA-EPSC kinetics or sensitivity to cyclothiazide. Pflugers Arch. 1999 Jan;437(2):191-6. Pubmed
  2. Rammes G, Swandulla D, Collingridge GL, Hartmann S, Parsons CG: Interactions of 2,3-benzodiazepines and cyclothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices. Br J Pharmacol. 1996 Mar;117(6):1209-21. Pubmed
  3. Fleck MW, Bahring R, Patneau DK, Mayer ML: AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to cyclothiazide. J Neurophysiol. 1996 Jun;75(6):2322-33. Pubmed
  4. Pirotte B, Podona T, Diouf O, de Tullio P, Lebrun P, Dupont L, Somers F, Delarge J, Morain P, Lestage P, Lepagnol J, Spedding M: 4H-1,2,4-Pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4H-1,2, 4-pyridothiadiazine 1,1-dioxides chemically related to diazoxide and cyclothiazide as powerful positive allosteric modulators of (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors: design, synthesis, pharmacology, and structure-activity relationships. J Med Chem. 1998 Jul 30;41(16):2946-59. Pubmed
  5. Larson J, Le TT, Hall RA, Lynch G: Effects of cyclothiazide on synaptic responses in slices of adult and neonatal rat hippocampus. Neuroreport. 1994 Jan 12;5(4):389-92. 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. Liljequist S, Cebers G, Kalda A: Effects of decahydroisoquinoline-3-carboxylic acid monohydrate, a novel AMPA receptor antagonist, on glutamate-induced CA2+ responses and neurotoxicity in rat cortical and cerebellar granule neurons. Biochem Pharmacol. 1995 Nov 27;50(11):1761-74. Pubmed
  2. 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

Transporters

1. Solute carrier family 22 member 6

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 6 Q4U2R8 Details

References:

  1. Uwai Y, Saito H, Hashimoto Y, Inui KI: Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther. 2000 Oct;295(1):261-5. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 10, 2014 11:01