Identification
- Summary
Brotizolam is a benzodiazepine analogue with sedative-hypnotic properties used for short-term treatment of severe or debilitating insomnia.
- Generic Name
- Brotizolam
- DrugBank Accession Number
- DB09017
- Background
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- Investigational, Withdrawn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
Structure for Brotizolam (DB09017)
- 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.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Insomnia •••••••••••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Not Available
- Mechanism of action
Target Actions Organism AGABA(A) Receptor positive allosteric modulatorHumans AGABA(A) Receptor Benzodiazepine Binding Site ligandHumans - 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
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 Brotizolam is combined with 1,2-Benzodiazepine. Abametapir The serum concentration of Brotizolam can be increased when it is combined with Abametapir. Acetazolamide The risk or severity of CNS depression can be increased when Acetazolamide is combined with Brotizolam. Acetophenazine The risk or severity of CNS depression can be increased when Acetophenazine is combined with Brotizolam. Agomelatine The risk or severity of CNS depression can be increased when Agomelatine is combined with Brotizolam. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- 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
- Benzodiazepine hypnotics and sedatives
- Benzodiazepines and benzodiazepine derivatives
- Central Nervous System Agents
- Central Nervous System Depressants
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Hypnotics and Sedatives
- Nervous System
- Psycholeptics
- 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
- Affected organisms
- 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[8.3.0.0^{2,6}]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
- 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. [Article]
- External Links
- KEGG Drug
- D01744
- PubChem Compound
- 2451
- PubChem Substance
- 310264974
- ChemSpider
- 2357
- BindingDB
- 50011875
- 19790
- ChEBI
- 31308
- ChEMBL
- CHEMBL32479
- ZINC
- ZINC000002570830
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Brotizolam
- MSDS
- Download (316 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Completed Treatment Sleep Initiation and Maintenance Disorders 1 3 Terminated Treatment Anxiety Disorders / Dementia / Depression / Psychosomatic Disorders / Schizophrenia 1 3 Unknown Status Prevention Insomnia 1 1 Completed Treatment Healthy Subjects (HS) 4 Not Available Completed Not Available Sleep Initiation and Maintenance Disorders 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet Oral 0.25 mg Tablet Oral 0.250 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US4094984 No 1978-06-13 1994-03-02 US 
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 211-213 U.S. Patent 4,094,984. - Predicted Properties
Property Value Source Water Solubility 0.058 mg/mL ALOGPS logP 3.28 ALOGPS logP 3.9 Chemaxon logS -3.8 ALOGPS pKa (Strongest Acidic) 18.38 Chemaxon pKa (Strongest Basic) 3.82 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 43.07 Å2 Chemaxon Rotatable Bond Count 1 Chemaxon Refractivity 101.93 m3·mol-1 Chemaxon Polarizability 34.99 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
- Not Available
Spectra
- Mass Spec (NIST)
- Download (85.7 KB)
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 166.1248 predictedDeepCCS 1.0 (2019) [M+H]+ 168.4828 predictedDeepCCS 1.0 (2019) [M+Na]+ 175.33598 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights 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
- 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
- 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
- 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]
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
- Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
Drug created at June 23, 2014 20:43 / Updated at May 27, 2021 02:57