Identification

Name
Ethoxzolamide
Accession Number
DB00311  (APRD00732, DB07727)
Type
Small Molecule
Groups
Withdrawn
Description

A carbonic anhydrase inhibitor used as diuretic and in glaucoma. It may cause hypokalemia. [PubChem]

Structure
Thumb
Synonyms
  • 6-Ethoxy-1,3-benzothiazole-2-sulfonamide
  • Ethoxazolamide
  • Ethoxyzolamide
International/Other Brands
Cardrase (PHARMACIA AND UPJOHN) / Ethamide (ALLERGAN)
Categories
UNII
Z52H4811WX
CAS number
452-35-7
Weight
Average: 258.317
Monoisotopic: 258.013283576
Chemical Formula
C9H10N2O3S2
InChI Key
OUZWUKMCLIBBOG-UHFFFAOYSA-N
InChI
InChI=1S/C9H10N2O3S2/c1-2-14-6-3-4-7-8(5-6)15-9(11-7)16(10,12)13/h3-5H,2H2,1H3,(H2,10,12,13)
IUPAC Name
6-ethoxy-1,3-benzothiazole-2-sulfonamide
SMILES
CCOC1=CC2=C(C=C1)N=C(S2)S(N)(=O)=O

Pharmacology

Indication

For use in the treatment of duodenal ulcers, as a diuretic, and in the treatment of glaucoma, and may also be useful in the treatment of seizures associated with epilepsy.

Pharmacodynamics

Ethoxzolamide, a sulfonamide, inhibits carbonic anhydrase activity in proximal renal tubules to decrease reabsorption of water, sodium, potassium, bicarbonate. It also decreases carbonic anhydrase in the CNS, increasing the seizure threshold. This reduction in carbonic anhydrase also reduces the intraocular pressure in the eye by decreasing aqueous humor.

Mechanism of action

Ethoxzolamide binds and inhibits carbonic anhydrase I. Carbonic anhydrase plays an essential role in facilitating the transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the layers of the extracellular space. The inhibition of this enzyme effects the balance of applicable membrane equilibrium systems. This reduction in carbonic anhydrase also reduces the intraocular pressure in the eye by decreasing aqueous humor.

TargetActionsOrganism
ACarbonic anhydrase 1
inhibitor
Human
ACarbonic anhydrase 2
inhibitor
Human
ACarbonic anhydrase 4
inhibitor
Human
ACarbonic anhydrase 7
inhibitor
Human
UCarbonic anhydrase 3
inhibitor
Human
Absorption

Rapidly absorbed with 65% bioavailability

Volume of distribution
Not Available
Protein binding

~89%

Metabolism
Not Available
Route of elimination
Not Available
Half life

2.5-5.5 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be increased when used in combination with Ethoxzolamide.
2,5-Dimethoxy-4-ethylamphetamineEthoxzolamide may decrease the excretion rate of 2,5-Dimethoxy-4-ethylamphetamine which could result in a higher serum level.
2,5-Dimethoxy-4-ethylthioamphetamineEthoxzolamide may decrease the excretion rate of 2,5-Dimethoxy-4-ethylthioamphetamine which could result in a higher serum level.
3,4-MethylenedioxyamphetamineEthoxzolamide may decrease the excretion rate of 3,4-Methylenedioxyamphetamine which could result in a higher serum level.
4-Bromo-2,5-dimethoxyamphetamineEthoxzolamide may decrease the excretion rate of 4-Bromo-2,5-dimethoxyamphetamine which could result in a higher serum level.
AcarboseThe therapeutic efficacy of Acarbose can be increased when used in combination with Ethoxzolamide.
AcemetacinThe therapeutic efficacy of Ethoxzolamide can be decreased when used in combination with Acemetacin.
AcetazolamideThe risk or severity of adverse effects can be increased when Ethoxzolamide is combined with Acetazolamide.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be increased when used in combination with Ethoxzolamide.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Ethoxzolamide.
Food Interactions
Not Available

References

Synthesis Reference

Korman, J.; U.S. Patent 2,868,800; January 13, 1959; assigned to The Upjohn Company.

General References
Not Available
External Links
Human Metabolome Database
HMDB0014456
KEGG Drug
D02441
PubChem Compound
3295
PubChem Substance
46509023
ChemSpider
3179
BindingDB
10882
ChEBI
101096
ChEMBL
CHEMBL18
Therapeutic Targets Database
DAP000598
PharmGKB
PA164754743
HET
EZL
Wikipedia
Ethoxzolamide
PDB Entries
3caj / 3dcw / 3dd0 / 3mdz / 5jn9 / 5tt3 / 6bcc

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
  • Pharmacia and upjohn co
  • Allergan pharmaceutical
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)188-190.5Korman, J.; U.S. Patent 2,868,800; January 13, 1959; assigned to The Upjohn Company.
water solubility40 mg/LYALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.01HANSCH,C ET AL. (1995)
logS-3.81ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility0.688 mg/mLALOGPS
logP1.87ALOGPS
logP1.6ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)7.51ChemAxon
pKa (Strongest Basic)-1.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area82.28 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity59.97 m3·mol-1ChemAxon
Polarizability25.27 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.8667
Caco-2 permeable-0.6038
P-glycoprotein substrateNon-substrate0.6875
P-glycoprotein inhibitor INon-inhibitor0.8793
P-glycoprotein inhibitor IINon-inhibitor0.9528
Renal organic cation transporterNon-inhibitor0.8576
CYP450 2C9 substrateNon-substrate0.8346
CYP450 2D6 substrateNon-substrate0.7982
CYP450 3A4 substrateNon-substrate0.6017
CYP450 1A2 substrateInhibitor0.6223
CYP450 2C9 inhibitorInhibitor0.62
CYP450 2D6 inhibitorNon-inhibitor0.8842
CYP450 2C19 inhibitorInhibitor0.6582
CYP450 3A4 inhibitorNon-inhibitor0.6471
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5599
Ames testNon AMES toxic0.5832
CarcinogenicityNon-carcinogens0.7065
BiodegradationNot ready biodegradable0.9846
Rat acute toxicity2.5056 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9429
hERG inhibition (predictor II)Non-inhibitor0.8419
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (10.1 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0uk9-3900000000-26213ae94b481c876007

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzothiazoles. These are organic compounds containing a benzene fused to a thiazole ring (a five-membered ring with four carbon atoms, one nitrogen atom and one sulfur atom).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzothiazoles
Sub Class
Not Available
Direct Parent
Benzothiazoles
Alternative Parents
Alkyl aryl ethers / Organosulfonamides / Benzenoids / Thiazoles / Heteroaromatic compounds / Aminosulfonyl compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 1 more
Substituents
1,3-benzothiazole / Alkyl aryl ether / Organosulfonic acid amide / Benzenoid / Azole / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Sulfonyl / Thiazole / Aminosulfonyl compound
show 12 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
benzothiazoles, sulfonamide (CHEBI:101096)

Targets

Details
1. Carbonic anhydrase 1
Kind
Protein
Organism
Human
Pharmacological action
Yes
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
References
  1. Kohling R, Vreugdenhil M, Bracci E, Jefferys JG: Ictal epileptiform activity is facilitated by hippocampal GABAA receptor-mediated oscillations. J Neurosci. 2000 Sep 15;20(18):6820-9. [PubMed:10995826]
  2. Perez Velazquez JL: Bicarbonate-dependent depolarizing potentials in pyramidal cells and interneurons during epileptiform activity. Eur J Neurosci. 2003 Sep;18(5):1337-42. [PubMed:12956733]
  3. Heck RW, Tanhauser SM, Manda R, Tu C, Laipis PJ, Silverman DN: Catalytic properties of mouse carbonic anhydrase V. J Biol Chem. 1994 Oct 7;269(40):24742-6. [PubMed:7929150]
  4. Siffert W, Gros G: Carbonic anhydrase C in white-skeletal-muscle tissue. Biochem J. 1982 Sep 1;205(3):559-66. [PubMed:6816217]
  5. Scozzafava A, Briganti F, Ilies MA, Supuran CT: Carbonic anhydrase inhibitors: synthesis of membrane-impermeant low molecular weight sulfonamides possessing in vivo selectivity for the membrane-bound versus cytosolic isozymes. J Med Chem. 2000 Jan 27;43(2):292-300. [PubMed:10649985]
  6. Bertucci A, Innocenti A, Zoccola D, Scozzafava A, Tambutte S, Supuran CT: Carbonic anhydrase inhibitors. Inhibition studies of a coral secretory isoform by sulfonamides. Bioorg Med Chem. 2009 Jul 15;17(14):5054-8. doi: 10.1016/j.bmc.2009.05.063. Epub 2009 May 30. [PubMed:19520577]
Details
2. Carbonic anhydrase 2
Kind
Protein
Organism
Human
Pharmacological action
Yes
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. Mincione F, Scozzafava A, Supuran CT: The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. Curr Pharm Des. 2008;14(7):649-54. [PubMed:18336310]
Details
3. Carbonic anhydrase 4
Kind
Protein
Organism
Human
Pharmacological action
Yes
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
References
  1. Mincione F, Scozzafava A, Supuran CT: The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. Curr Pharm Des. 2008;14(7):649-54. [PubMed:18336310]
Details
4. Carbonic anhydrase 7
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide.
Gene Name
CA7
Uniprot ID
P43166
Uniprot Name
Carbonic anhydrase 7
Molecular Weight
29658.235 Da
References
  1. Mincione F, Scozzafava A, Supuran CT: The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. Curr Pharm Des. 2008;14(7):649-54. [PubMed:18336310]
Details
5. Carbonic anhydrase 3
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Reversible hydration of carbon dioxide.
Gene Name
CA3
Uniprot ID
P07451
Uniprot Name
Carbonic anhydrase 3
Molecular Weight
29557.215 Da
References
  1. Nishimori I, Minakuchi T, Onishi S, Vullo D, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors: cloning, characterization, and inhibition studies of the cytosolic isozyme III with sulfonamides. Bioorg Med Chem. 2007 Dec 1;15(23):7229-36. Epub 2007 Aug 25. [PubMed:17826101]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
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:10991988]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:41