Explore a selection of our essential drug information below, or:
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
Structure for Cloxazolam (DB01553)
- 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.
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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.
Target Actions Organism AGABA(A) Receptor positive allosteric modulatorHumans AGABA(A) Receptor Benzodiazepine Binding Site ligandHumans - 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
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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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Cloxazolam is combined with 1,2-Benzodiazepine. Acetazolamide The risk or severity of CNS depression can be increased when Acetazolamide is combined with Cloxazolam. Acetophenazine The risk or severity of CNS depression can be increased when Acetophenazine is combined with Cloxazolam. Agomelatine The risk or severity of CNS depression can be increased when Cloxazolam is combined with Agomelatine. Alfentanil The risk or severity of adverse effects can be increased when Alfentanil is combined with Cloxazolam. - Food Interactions
- Avoid alcohol. Alcohol can increase CNS depressant effects, such as fatal respiratory or cardiac depression.
Products
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- 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[8.4.0.0^{2,6}]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
- Ansseau M, von Frenckell R: Controlled comparison of two anxiolytic benzodiazepines, cloxazolam and bromazepam. Neuropsychobiology. 1990-1991;24(1):25-9. [Article]
- 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]
- Ito M, Miyajima T, Fujii T, Okuno T: Cloxazolam treatment for patients with intractable epilepsy. Pediatr Neurol. 2004 Feb;30(2):111-4. [Article]
- 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]
- 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]
- External Links
- Human Metabolome Database
- HMDB0259410
- KEGG Drug
- D01268
- PubChem Compound
- 2816
- PubChem Substance
- 46505281
- ChemSpider
- 2714
- BindingDB
- 220121
- 21311
- ChEBI
- 31426
- ChEMBL
- CHEMBL2107254
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Cloxazolam
Clinical Trials
- Clinical Trials
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Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet Oral 1 mg Tablet Oral 2 mg Tablet Oral 4 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 202-204 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. - Predicted Properties
Property Value Source Water Solubility 0.0266 mg/mL ALOGPS logP 3.56 ALOGPS logP 4.13 Chemaxon logS -4.1 ALOGPS pKa (Strongest Acidic) 12.69 Chemaxon pKa (Strongest Basic) 2.71 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 41.57 Å2 Chemaxon Rotatable Bond Count 1 Chemaxon Refractivity 91.05 m3·mol-1 Chemaxon Polarizability 33.62 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9711 Caco-2 permeable + 0.5998 P-glycoprotein substrate Substrate 0.6791 P-glycoprotein inhibitor I Inhibitor 0.7361 P-glycoprotein inhibitor II Inhibitor 0.6386 Renal organic cation transporter Non-inhibitor 0.513 CYP450 2C9 substrate Non-substrate 0.82 CYP450 2D6 substrate Non-substrate 0.775 CYP450 3A4 substrate Substrate 0.7551 CYP450 1A2 substrate Inhibitor 0.7755 CYP450 2C9 inhibitor Inhibitor 0.7065 CYP450 2D6 inhibitor Non-inhibitor 0.5945 CYP450 2C19 inhibitor Inhibitor 0.8156 CYP450 3A4 inhibitor Inhibitor 0.5 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8 Ames test Non AMES toxic 0.6803 Carcinogenicity Non-carcinogens 0.7912 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.2614 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9597 hERG inhibition (predictor II) Inhibitor 0.6805
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 172.83882 predictedDeepCCS 1.0 (2019) [M+H]+ 175.19682 predictedDeepCCS 1.0 (2019) [M+Na]+ 181.28996 predictedDeepCCS 1.0 (2019)
Targets
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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
- Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:29950725, PubMed:30602789). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:23909897, PubMed:29950725, PubMed:30602789). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:23909897, PubMed:25489750). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (By similarity)
- Specific Function
- GABA-A receptor activity
Components:
References
- 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]
- 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
- Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:29950725, PubMed:30602789). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:23909897, PubMed:29950725, PubMed:30602789). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:23909897, PubMed:25489750). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (By similarity)
- Specific Function
- GABA-A receptor activity
Components:
References
- 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]
- 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 at July 31, 2007 13:10 / Updated at October 07, 2024 17:35