Identification

Name
Brotizolam
Accession Number
DB09017
Description

Brotizolam is a sedative-hypnotic thienodiazepine drug which is a benzodiazepine analog. It demonstrates anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant effects. Brotizolam has similar effects to short-acting benzodiazepines such as triazolam. Brotizolam is indicated for 2-4 weeks of treatment for severe or debilitating insomnia. Brotizolam is an extremely potent drug and it is rapidly eliminated with an average half-life of 4.4 hours (range 3.6 - 7.9 hours).

Brotizolam is not approved for sale in the UK, United States or Canada but is sold in the Netherlands, Germany, Spain, Belgium, Austria, Portugal, Israel, Italy and Japan.

Type
Small Molecule
Groups
Investigational, Withdrawn
Structure
Thumb
Weight
Average: 393.689
Monoisotopic: 391.949807384
Chemical Formula
C15H10BrClN4S
Synonyms
  • Brotizolam
  • Brotizolamum
External IDs
  • SID144207150
  • WE 941
  • WE 941-BS
  • WE-941
  • WE-941-BS

Pharmacology

Indication

Brotizolam is indicated for 2-4 weeks in the treatment of severe or debilitating insomnia.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics
Not Available
Mechanism of action
TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
AGABA(A) Receptor Benzodiazepine Binding Site
ligand
Humans
Absorption

The plasma concentration profile of brotizolam can be described as a one compartmental open model with first-order absorption.

Volume of distribution

0.63 l/kg.

Protein binding

The mean value of the free fraction (%): 8.4 ± 0.7.

Metabolism

There are two primary metabolites: 1-methyl-hydroxy- and the 4-hydroxy-derivatives (Eberts et al., 1981; Boehringer Ingelheim, product information). The 4-hydroxymetabolites have a pharmacological activity which is far less than that of the parent drugs, but the 1-methyl-hydroxymetabolites probably have comparable activity (Gall et al., 1978; Jochemsen et al., 1982; Sethy & Harris, 1982; Jochemsen et al., unpublished results). These active compounds are, however, not present in plasma in measurable amounts following a single dose of brotizolam to young healthy subjects (Jochemsen et al., 1982; Jochemsen et al., unpublished results).

Route of elimination
Not Available
Half-life

4.4 hours.

Clearance

Total clearance: 109 ml/min.

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity
Not Available
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
AbametapirThe serum concentration of Brotizolam can be increased when it is combined with Abametapir.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Brotizolam.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Brotizolam.
AclidiniumBrotizolam may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AgomelatineThe risk or severity of adverse effects can be increased when Agomelatine is combined with Brotizolam.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Brotizolam.
AlimemazineThe risk or severity of adverse effects can be increased when Alimemazine is combined with Brotizolam.
AlmotriptanThe risk or severity of adverse effects can be increased when Almotriptan is combined with Brotizolam.
AlosetronThe risk or severity of adverse effects can be increased when Alosetron is combined with Brotizolam.
AlprazolamThe risk or severity of adverse effects can be increased when Alprazolam is combined with Brotizolam.
Additional Data Available
  • Extended Description
    Extended Description

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

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  • 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
Not Available

Products

International/Other Brands
Amnezon (Nisshin Seiyaku) / Bondormin (Rafa) / Brometon (Mylan Seiyaku) / Brotizolam M (Sannova) / Dormex (Recalcine) / Eurimolan (Choseido Pharmaceutical) / Goodmin (Tanabe Mitsubishi Pharma) / Lendorm (Boehringer Ingelheim) / Lendormin (Boehringer Ingelheim) / Lindormin (Boehringer Ingelheim) / Nestrom (Tatsumi Kagaku) / Noctilan (Boehringer Ingelheim) / Noxtal (Alfresa Pharma) / Ronfleman (Kyowa Yakuhin) / Sintonal (Europharma) / Sorentmin (Taisho Yakuhin) / Zestromin (Towa Yakuhin)

Categories

ATC Codes
N05CD09 — Brotizolam
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as thienodiazepines. These are heteropolycyclic containing a thiophene ring fused to a diazepine ring. Thiophene is 5-membered ring consisting of four carbon and one sulfur atoms. Diazepine is a 7-membered ring consisting of five carbon and two nitrogen atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Thienodiazepines
Sub Class
Not Available
Direct Parent
Thienodiazepines
Alternative Parents
2,3,5-trisubstituted thiophenes / Chlorobenzenes / 1,4-diazepines / Aryl chlorides / Aryl bromides / Triazoles / Heteroaromatic compounds / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds
show 4 more
Substituents
1,2,4-triazole / 2,3,5-trisubstituted thiophene / Aromatic heteropolycyclic compound / Aryl bromide / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid / Chlorobenzene
show 17 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
5XZM1R3DKF
CAS number
57801-81-7
InChI Key
UMSGKTJDUHERQW-UHFFFAOYSA-N
InChI
InChI=1S/C15H10BrClN4S/c1-8-19-20-13-7-18-14(9-4-2-3-5-11(9)17)10-6-12(16)22-15(10)21(8)13/h2-6H,7H2,1H3
IUPAC Name
4-bromo-7-(2-chlorophenyl)-13-methyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaene
SMILES
CC1=NN=C2CN=C(C3=C(SC(Br)=C3)N12)C1=CC=CC=C1Cl

References

Synthesis Reference

Brotizolam synthesis: Weber, K. H.; Bauer, A.; Danneberg, P.; Kuhn, F. J.; 1978, U.S. Patent 4,094,984.

General References
  1. Jochemsen R, Wesselman JG, van Boxtel CJ, Hermans J, Breimer DD: Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects. Br J Clin Pharmacol. 1983;16 Suppl 2:291S-297S. [PubMed:6140948]
KEGG Drug
D01744
PubChem Compound
2451
PubChem Substance
310264974
ChemSpider
2357
BindingDB
50011875
RxNav
19790
ChEBI
31308
ChEMBL
CHEMBL32479
ZINC
ZINC000002570830
Drugs.com
Drugs.com Drug Page
Wikipedia
Brotizolam
MSDS
Download (316 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentSleep Initiation and Maintenance Disorders1
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenia1
3Unknown StatusPreventionInsomnia1
1CompletedTreatmentHealthy Volunteers4
Not AvailableCompletedNot AvailableSleep Initiation and Maintenance Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet0.25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US4094984No1978-06-131994-03-02US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)211-213U.S. Patent 4,094,984.
Predicted Properties
PropertyValueSource
Water Solubility0.058 mg/mLALOGPS
logP3.28ALOGPS
logP2.68ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)18.49ChemAxon
pKa (Strongest Basic)3.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area43.07 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity101.93 m3·mol-1ChemAxon
Polarizability34.99 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Download (85.7 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Mass Spectrum (Electron Ionization)MSsplash10-0006-6559000000-7456ba6570cdfa674b63
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

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. [PubMed:23038269]
  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. [PubMed:29950725]
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. [PubMed:23038269]
  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. [PubMed:29950725]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]

Drug created on June 23, 2014 14:43 / Updated on June 12, 2020 10:52

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