Ketazolam

Identification

Summary

Ketazolam is a long-acting benzodiazepine used to manage anxiety and insomnia.

Generic Name
Ketazolam
DrugBank Accession Number
DB01587
Background

Ketazolam is a benzodiazepine derivative with anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant activity. Ketazolam is not approved in Canada or America.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 368.814
Monoisotopic: 368.092770127
Chemical Formula
C20H17ClN2O3
Synonyms
  • Ketazolam
  • Ketazolamum
External IDs
  • U-28,774
  • U-28774

Pharmacology

Indication

Ketazolam could be used for the treatment of anxiety. In approved countries, it is indicated for the treatment of anxiety, tension, irritability and similar stress related symptoms.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAnxiety•••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA), which results in sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant and amnesic action. Benzodiazepines bind nonspecifically to benzodiazepine receptors which mediate sleep, affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

Mechanism of action

Benzodiazepines share a similar chemical structure and their effects in humans are mainly produced by the allosteric modification of a specific kind of neurotransmitter receptor, the GABAA receptor, which increases the conductance of this inhibitory channel; this results in the various therapeutic effects as well as adverse effects of benzodiazepines. Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the conduction of chloride ions across the neuronal cell membrane. This increased conductance raises the membrane potential of the neuron resulting in inhibition of neuronal firing. In addition, different GABAA receptor subtypes have varying distributions within different regions of the brain and therefore control distinct neuronal circuits. Hence, activation of different GABAA receptor subtypes by benzodiazepines may result in distinct pharmacological actions.

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

Ketazolam is metabolized to diazepam, followed by demoxepam, and finally desmethyldiazepam.

Route of elimination

Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates.

Half-life

26-200 hours

Clearance

Not Available

Adverse Effects
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Toxicity

Symptoms of overdose include somnolence, confusion, coma, and diminished reflexes. Respiration, pulse and blood pressure should be monitored.

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 CNS depression can be increased when Ketazolam is combined with 1,2-Benzodiazepine.
AbacavirAbacavir may decrease the excretion rate of Ketazolam which could result in a higher serum level.
AbametapirThe serum concentration of Ketazolam can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Ketazolam.
AcalabrutinibThe serum concentration of Acalabrutinib can be increased when it is combined with Ketazolam.
Food Interactions
  • Avoid alcohol.
  • Avoid grapefruit products.
  • Limit caffeine intake.
  • Take with food.

Products

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International/Other Brands
Anseren (Novartis) / Ansieten (Ivax) / Ansietil (Medicamenta Ecuatoriana, Ecuador) / Atenual (Tecnofarma) / Loftran / Marcen (Vegal) / Sedatival F.P. (Recalcine) / Sedavital (Farmindustria) / Sedotime (Faes) / Solatran (GlaxoSmithKline) / Unakalm (Tecnifar)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Loftran Cap 30mgCapsule30 mg / capOralSmithkline Beecham Pharma Division Of Smithkline Beecham Inc1992-12-311996-09-12Canada flag

Categories

ATC Codes
N05BA10 — Ketazolam
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1,4-benzodiazepines. These are organic compounds containing a benzene ring fused to a 1,4-azepine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
1,4-benzodiazepines
Direct Parent
1,4-benzodiazepines
Alternative Parents
Alpha amino acids and derivatives / Benzene and substituted derivatives / Aryl chlorides / Vinylogous esters / Tertiary carboxylic acid amides / Lactams / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds
show 4 more
Substituents
1,4-benzodiazepine / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
92A214MD7Y
CAS number
27223-35-4
InChI Key
PWAJCNITSBZRBL-UHFFFAOYSA-N
InChI
InChI=1S/C20H17ClN2O3/c1-13-10-18(24)23-12-19(25)22(2)17-9-8-15(21)11-16(17)20(23,26-13)14-6-4-3-5-7-14/h3-11H,12H2,1-2H3
IUPAC Name
14-chloro-4,10-dimethyl-2-phenyl-3-oxa-7,10-diazatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),4,12,14-tetraene-6,9-dione
SMILES
CN1C2=C(C=C(Cl)C=C2)C2(OC(C)=CC(=O)N2CC1=O)C1=CC=CC=C1

References

Synthesis Reference

U.S. Patent 3,575,965.

General References
Not Available
Human Metabolome Database
HMDB0015526
PubChem Compound
33746
PubChem Substance
46507008
ChemSpider
31110
RxNav
28181
ChEBI
135556
ChEMBL
CHEMBL2104356
PharmGKB
PA164749385
Wikipedia
Ketazolam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral15 MG
CapsuleOral30 MG
CapsuleOral45 MG
CapsuleOral30 mg / cap
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)174-176U.S. Patent 3,575,965.
Predicted Properties
PropertyValueSource
Water Solubility0.0839 mg/mLALOGPS
logP2.6ALOGPS
logP3.01Chemaxon
logS-3.6ALOGPS
pKa (Strongest Acidic)14.2Chemaxon
pKa (Strongest Basic)-1.5Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area49.85 Å2Chemaxon
Rotatable Bond Count1Chemaxon
Refractivity99.78 m3·mol-1Chemaxon
Polarizability36.96 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9965
Blood Brain Barrier+0.9382
Caco-2 permeable+0.7069
P-glycoprotein substrateSubstrate0.7006
P-glycoprotein inhibitor IInhibitor0.6305
P-glycoprotein inhibitor IINon-inhibitor0.8837
Renal organic cation transporterNon-inhibitor0.7534
CYP450 2C9 substrateNon-substrate0.8193
CYP450 2D6 substrateNon-substrate0.8504
CYP450 3A4 substrateSubstrate0.7504
CYP450 1A2 substrateNon-inhibitor0.5878
CYP450 2C9 inhibitorInhibitor0.5154
CYP450 2D6 inhibitorNon-inhibitor0.9257
CYP450 2C19 inhibitorInhibitor0.5938
CYP450 3A4 inhibitorInhibitor0.6037
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.52
Ames testNon AMES toxic0.7228
CarcinogenicityNon-carcinogens0.789
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.8992 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9935
hERG inhibition (predictor II)Non-inhibitor0.8687
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
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0fri-7794000000-e5f97e7007c42a0e6cae
Mass Spectrum (Electron Ionization)MSsplash10-0a59-1290000000-7ef8a75bf466c745a728
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0009000000-ad82dc7a020c84692812
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0009000000-a5dd4aa516f497e2ba38
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0009000000-254f82c7441d9c32f296
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-016r-0009000000-2ba5955e94df3cd6b79f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0553-0369000000-50dc465eaa5f98f4f84f
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-014l-2129000000-5e96cb3c6794eabcf56e
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-184.6994775
predicted
DarkChem Lite v0.1.0
[M-H]-182.66722
predicted
DeepCCS 1.0 (2019)
[M+H]+185.1329775
predicted
DarkChem Lite v0.1.0
[M+H]+185.02522
predicted
DeepCCS 1.0 (2019)
[M+Na]+184.9108775
predicted
DarkChem Lite v0.1.0
[M+Na]+191.73105
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Dinis-Oliveira RJ: Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects. Drug Metab Rev. 2017 Nov;49(4):451-463. doi: 10.1080/03602532.2017.1377223. Epub 2017 Sep 14. [Article]
  2. Flockhart Table of Drug Interactions [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. [Article]
  2. Brodersen R, Honore B: Drug binding properties of neonatal albumin. Acta Paediatr Scand. 1989 May;78(3):342-6. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Yamazaki M, Neway WE, Ohe T, Chen I, Rowe JF, Hochman JH, Chiba M, Lin JH: In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results. J Pharmacol Exp Ther. 2001 Mar;296(3):723-35. [Article]
  2. Adachi Y, Suzuki H, Sugiyama Y: Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8. [Article]

Drug created at August 29, 2007 15:28 / Updated at June 12, 2020 16:51