Cloxazolam

Identification

Generic Name
Cloxazolam
DrugBank Accession Number
DB01553
Background

Cloxazolam is a benzodiazepine with anxiolytic, sedative/hypnotic, muscle relaxant, and antiepileptic effects. It is marketed in the Argentina, Australia, Portugal, Belgium, Switzerland, Luxembourg, Germany, Taiwan and Japan -- mainly for anti-anxiety. The usual dose of cloxazolam in adults is 3-12mg/day for anti-anxiety. Although less commonly noted, it has also been reported as clinically effective in the treatment of depression, schizophrenia, and neurosis. As well, it has also been studied in Japan in doses of 15-30mg/day as an adjunct in the treatment of intractable epilepsy, for which it has demonstrated effectiveness.

Type
Small Molecule
Groups
Experimental
Structure
Thumb
Weight
Average: 349.211
Monoisotopic: 348.043233116
Chemical Formula
C17H14Cl2N2O2
Synonyms
  • Cloxazolam
  • Cloxazolamum
  • Cloxazolazepam
External IDs
  • CS-370
  • MT 14-411

Pharmacology

Indication

Used primarily as an anti-anxiety agent. Typically used short term, and may be given as a single dose of up to 100mcg/kg to reduce anxiety and tension experienced prior to surgery.

Pharmacology
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Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Studies have shown a superiority of 4mg/day of cloxazepam to 12mg/day of bromazepam in terms of anxiety, depressed mood, and sleep; an insignificant difference in terms of sedative effect; and less muscle relaxant effects. [3]

Cloxazolam, administered as a single oral dose of 3mg, when compared to a single 5 mg dose of diazepam in one study, showed similar subjective measures; however, there cloxazolam caused more fatigue, and less mood improvement. Cloxazolam also induced a significant increase in heart rate in the control group of this study. [3]

Mechanism of action

Cloxazolam is a long acting benzodiazepine. It acts as a prodrug, with pharmacologically active metabolites, which bind to to the GABAa receptor, which other benzodiazepines bind to, to illicit a physiological response. [wiki]

TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
AGABA(A) Receptor Benzodiazepine Binding Site
ligand
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Cloxazolam is metabolised by the liver into the active metabolite chlordesmethyldiazepam (delorazepam). [5]

Route of elimination

Renal elimination.

Half-life

65 hours

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Drowsiness and ataxia are dose related. Central nervous system toxicity may result in respiratory depression and loss of consciousness. As such, pre-existing central nervous system depression and severe hepatic impairment are two particular contraindications for use.

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
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Cloxazolam is combined with 1,2-Benzodiazepine.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Cloxazolam.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Cloxazolam.
AclidiniumCloxazolam may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AgomelatineThe risk or severity of adverse effects can be increased when Cloxazolam is combined with Agomelatine.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Cloxazolam.
AlimemazineThe risk or severity of adverse effects can be increased when Alimemazine is combined with Cloxazolam.
AlmotriptanThe risk or severity of adverse effects can be increased when Almotriptan is combined with Cloxazolam.
AlosetronThe risk or severity of adverse effects can be increased when Alosetron is combined with Cloxazolam.
AlprazolamThe risk or severity of adverse effects can be increased when Alprazolam is combined with Cloxazolam.
Interactions
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Food Interactions
  • Avoid alcohol. Alcohol can increase CNS depressant effects, such as fatal respiratory or cardiac depression.

Products

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International/Other Brands
Akton (Nycomed) / Cloxam (Jaba Recordati) / Clozal (Sankyo Pharma Brasil Ltda) / Elum (Farmasa) / Olcadil (Novartis) / Sepazon (Daiichi Sankyo) / Tolestan (Roemmers)

Categories

ATC Codes
N05BA22 — Cloxazolam
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1,3-oxazolobenzo-1,4-diazepines. These are aromatic heteropolycyclic compounds containing a 1,3-oxazole ring fused to the 1,-4-diazepine moiety of a 1,4-benzodiazepine ring system.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
1,4-benzodiazepines
Direct Parent
1,3-oxazolobenzo-1,4-diazepines
Alternative Parents
Chlorobenzenes / Aryl chlorides / Oxazolidines / Cyclic carboximidic acids / Propargyl-type 1,3-dipolar organic compounds / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds
show 2 more
Substituents
1,3-oxazolobenzo-1,4-diazepine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Chlorobenzene / Cyclic carboximidic acid / Halobenzene / Hydrocarbon derivative
show 12 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
oxazolobenzodiazepine (CHEBI:31426)
Affected organisms
Not Available

Chemical Identifiers

UNII
GYL649Z0HY
CAS number
24166-13-0
InChI Key
ZIXNZOBDFKSQTC-UHFFFAOYSA-N
InChI
InChI=1S/C17H14Cl2N2O2/c18-11-5-6-15-13(9-11)17(12-3-1-2-4-14(12)19)21(7-8-23-17)10-16(22)20-15/h1-6,9H,7-8,10H2,(H,20,22)
IUPAC Name
13-chloro-2-(2-chlorophenyl)-3-oxa-6,9-diazatricyclo[8.4.0.0²,⁶]tetradeca-1(10),11,13-trien-8-one
SMILES
ClC1=CC2=C(NC(=O)CN3CCOC23C2=CC=CC=C2Cl)C=C1

References

Synthesis Reference

Tachikawa, R., Takagi, H., Kamioka, T., Fukunaga, M., Kawano, Y. and Miyadera, T.; US. Patents 3,696,094; October 3,1972; and 3,772,371; November 13, 1973; both assigned to Sankyo Company Limited, Japan.

General References
  1. Ansseau M, von Frenckell R: Controlled comparison of two anxiolytic benzodiazepines, cloxazolam and bromazepam. Neuropsychobiology. 1990-1991;24(1):25-9. [Article]
  2. Boucsein W, Wendt-Suhl G: [Psychological and physiological effects of cloxazolam and diazepam under anxiety-evoking and control conditions on healthy subjects (author's transl)]. Pharmacopsychiatria. 1982 Mar;15(2):48-56. [Article]
  3. Ito M, Miyajima T, Fujii T, Okuno T: Cloxazolam treatment for patients with intractable epilepsy. Pediatr Neurol. 2004 Feb;30(2):111-4. [Article]
  4. Murata H, Kougo K, Yasumura A, Nakajma E, Shindo H: Metabolism of cloxazolam I. Distribution, excretion and biotransformation in rats and mice. Chem Pharm Bull (Tokyo). 1973 Feb;21(2):404-14. [Article]
  5. Oliveira-Silva D, Oliveira CH, Mendes GD, Galvinas PA, Barrientos-Astigarraga RE, De Nucci G: Quantification of chlordesmethyldiazepam by liquid chromatography-tandem mass spectrometry: application to a cloxazolam bioequivalence study. Biomed Chromatogr. 2009 Dec;23(12):1266-75. doi: 10.1002/bmc.1249. [Article]
KEGG Drug
D01268
PubChem Compound
2816
PubChem Substance
46505281
ChemSpider
2714
BindingDB
220121
RxNav
21311
ChEBI
31426
ChEMBL
CHEMBL2107254
Drugs.com
Drugs.com Drug Page
Wikipedia
Cloxazolam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
TabletOral1 mg
TabletOral2 mg
TabletOral4 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)202-204Tachikawa, R., Takagi, H., Kamioka, T., Fukunaga, M., Kawano, Y. and Miyadera, T.; US. Patents 3,696,094; October 3,1972; and 3,772,371; November 13, 1973; both assigned to Sankyo Company Limited, Japan.
Predicted Properties
PropertyValueSource
Water Solubility0.0266 mg/mLALOGPS
logP3.56ALOGPS
logP4.13ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)12.69ChemAxon
pKa (Strongest Basic)2.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area41.57 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity91.05 m3·mol-1ChemAxon
Polarizability33.62 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9711
Caco-2 permeable+0.5998
P-glycoprotein substrateSubstrate0.6791
P-glycoprotein inhibitor IInhibitor0.7361
P-glycoprotein inhibitor IIInhibitor0.6386
Renal organic cation transporterNon-inhibitor0.513
CYP450 2C9 substrateNon-substrate0.82
CYP450 2D6 substrateNon-substrate0.775
CYP450 3A4 substrateSubstrate0.7551
CYP450 1A2 substrateInhibitor0.7755
CYP450 2C9 inhibitorInhibitor0.7065
CYP450 2D6 inhibitorNon-inhibitor0.5945
CYP450 2C19 inhibitorInhibitor0.8156
CYP450 3A4 inhibitorInhibitor0.5
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8
Ames testNon AMES toxic0.6803
CarcinogenicityNon-carcinogens0.7912
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2614 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9597
hERG inhibition (predictor II)Inhibitor0.6805
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
Mass Spectrum (Electron Ionization)MSsplash10-0bt9-1493000000-ab9e03b63d47a52579ab
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

Targets

Drugtargets2
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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Positive allosteric modulator
Curator comments
The GABA(A) receptor is pentameric (i.e. comprising 5 subunit proteins) and therefore has a multitude of potential isoforms. The above target is a collection of all possible GABA(A) subunits that may participate in the formation of the pentameric receptor and is not meant to imply direct a drug-protein interaction for each individual subunit.
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
  2. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
Curator comments
Benzodiazepines modulate GABA(A) function by binding at the interface between alpha (α) and gamma (γ) subunits. Of the 6 α-subunits, only 4 (α-1, -2, -3, and -5) participate in the formation of this binding site. The above target is a collection of all α- and γ-subunits that are known to participate in the formation of the benzodiazepine binding site.
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
  2. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]

Drug created on July 31, 2007 13:10 / Updated on February 21, 2021 18:51