Identification

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Name
Ketazolam
Accession Number
DB01587
Type
Small Molecule
Groups
Approved
Description

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

Structure
Thumb
Synonyms
  • Ketazolam
  • Ketazolamum
External IDs
U-28,774 / U-28774
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Loftran Cap 30mgCapsuleOralSmithkline Beecham Pharma Division Of Smithkline Beecham Inc1992-12-311996-09-12Canada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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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)
Categories
UNII
92A214MD7Y
CAS number
27223-35-4
Weight
Average: 368.814
Monoisotopic: 368.092770127
Chemical Formula
C20H17ClN2O3
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[9.4.0.0²,⁷]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

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.

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
ATranslocator protein
agonist
Humans
AGamma-aminobutyric acid receptor subunit alpha-1
potentiator
Humans
AGamma-aminobutyric acid receptor subunit beta-1
potentiator
Humans
AGamma-aminobutyric acid receptor subunit gamma-1
potentiator
Humans
AGamma-aminobutyric acid receptor subunit delta
potentiator
Humans
AGamma-aminobutyric acid receptor subunit epsilon
potentiator
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
Toxicity

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

Affected organisms
Not Available
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
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Ketazolam.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Ketazolam.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Ketazolam is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe therapeutic efficacy of Ketazolam can be decreased when used in combination with 3-isobutyl-1-methyl-7H-xanthine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Ketazolam.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Ketazolam.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Ketazolam.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Ketazolam is combined with 5-methoxy-N,N-dimethyltryptamine.
6-O-benzylguanineThe therapeutic efficacy of Ketazolam can be decreased when used in combination with 6-O-benzylguanine.
7-DeazaguanineThe therapeutic efficacy of Ketazolam can be decreased when used in combination with 7-Deazaguanine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid alcohol
  • Avoid excessive quantities of coffee or tea (caffeine).
  • Avoid taking with grapefruit or grapefruit juice as grapefruit can significantly increase serum levels of this product.
  • Take with food.

References

Synthesis Reference

U.S. Patent 3,575,965.

General References
Not Available
External Links
Human Metabolome Database
HMDB0015526
PubChem Compound
33746
PubChem Substance
46507008
ChemSpider
31110
ChEBI
135556
ChEMBL
CHEMBL2104356
PharmGKB
PA164749385
Wikipedia
Ketazolam
ATC Codes
N05BA10 — Ketazolam

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral
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)-0.89ChemAxon
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-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-0a59-1290000000-7ef8a75bf466c745a728
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

Taxonomy

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 / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Tertiary carboxylic acid amide / Vinylogous ester / Carboxamide group / Lactam
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Cholesterol binding
Specific Function
Can bind protoporphyrin IX and may play a role in the transport of porphyrins and heme (By similarity). Promotes the transport of cholesterol across mitochondrial membranes and may play a role in l...
Gene Name
TSPO
Uniprot ID
P30536
Uniprot Name
Translocator protein
Molecular Weight
18827.81 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, Diaz G: Intracellular cholesterol changes induced by translocator protein (18 kDa) TSPO/PBR ligands. Neuropharmacology. 2007 Aug;53(2):318-29. Epub 2007 Jun 2. [PubMed:17631921]
  3. Vega D, Fernandez D, Echeverria G: Ketazolam. Acta Crystallogr C. 2001 Jul;57(Pt 7):848-50. Epub 2001 Jul 9. [PubMed:11443263]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Potentiator
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...
Gene Name
GABRA1
Uniprot ID
P14867
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-1
Molecular Weight
51801.395 Da
References
  1. Blaschke G, Kley H, Muller WE: [Racemation of the benzodiazepines camazepam and ketazolam and receptor binding of enantiomers]. Arzneimittelforschung. 1986 Jun;36(6):893-4. [PubMed:2874815]
  2. Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
  3. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
  4. Derry JM, Dunn SM, Davies M: Identification of a residue in the gamma-aminobutyric acid type A receptor alpha subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding. J Neurochem. 2004 Mar;88(6):1431-8. [PubMed:15009644]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Potentiator
General Function
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...
Gene Name
GABRB1
Uniprot ID
P18505
Uniprot Name
Gamma-aminobutyric acid receptor subunit beta-1
Molecular Weight
54234.085 Da
References
  1. Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
  2. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
  3. Derry JM, Dunn SM, Davies M: Identification of a residue in the gamma-aminobutyric acid type A receptor alpha subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding. J Neurochem. 2004 Mar;88(6):1431-8. [PubMed:15009644]
  4. Blaschke G, Kley H, Muller WE: [Racemation of the benzodiazepines camazepam and ketazolam and receptor binding of enantiomers]. Arzneimittelforschung. 1986 Jun;36(6):893-4. [PubMed:2874815]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Potentiator
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRG1
Uniprot ID
Q8N1C3
Uniprot Name
Gamma-aminobutyric acid receptor subunit gamma-1
Molecular Weight
53594.49 Da
References
  1. Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
  2. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Potentiator
General Function
Gaba-a receptor activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRD
Uniprot ID
O14764
Uniprot Name
Gamma-aminobutyric acid receptor subunit delta
Molecular Weight
50707.835 Da
References
  1. Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
  2. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Potentiator
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRE
Uniprot ID
P78334
Uniprot Name
Gamma-aminobutyric acid receptor subunit epsilon
Molecular Weight
57971.175 Da
References
  1. Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002 Jan;300(1):2-8. [PubMed:11752090]
  2. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. doi: 10.1111/j.1600-0404.2008.01004.x. Epub 2008 Mar 31. [PubMed:18384456]

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. [PubMed:28903606]
  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. [PubMed:9275312]
  2. Brodersen R, Honore B: Drug binding properties of neonatal albumin. Acta Paediatr Scand. 1989 May;78(3):342-6. [PubMed:2545072]

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. [PubMed:11181899]
  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. [PubMed:11785684]

Drug created on August 29, 2007 09:28 / Updated on November 02, 2019 00:53