Identification

Name
Estazolam
Accession Number
DB01215  (APRD00955)
Type
Small Molecule
Groups
Approved, Illicit
Description

A benzodiazepine with anticonvulsant, hypnotic, and muscle relaxant properties. It has been shown in some cases to be more potent than diazepam or nitrazepam.

Structure
Thumb
Synonyms
  • 8-chloro-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine
  • Estazolam
  • Estazolamum
External IDs
ABBOTT-47631
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ProsomTablet2 mg/1OralAbbvie1990-12-312008-03-31Us
ProsomTablet1 mg/1OralAbbvie1990-12-262008-03-31Us
Prosom Tab 1mgTabletOralAbbott1993-12-311997-08-18Canada
Prosom Tab 2mgTabletOralAbbott1993-12-311997-08-18Canada
Additional Data Available
  • Application Number
    Application Number

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

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  • Product Code
    Product Code

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

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EstazolamTablet1 mg/1OralTeva1997-07-142018-01-31Us00093 0129 01 nlmimage10 4842a445
EstazolamTablet2 mg/1OralPar Pharmaceutical2009-06-302009-06-30Us
EstazolamTablet1 mg/1OralPar Pharmaceutical2009-06-302009-06-30Us
EstazolamTablet2 mg/1OralPar Pharmaceutical2004-01-262006-01-26Us
EstazolamTablet1 mg/1OralPar Pharmaceutical2004-01-262006-01-26Us
EstazolamTablet2 mg/1OralRebel Distributors1997-08-19Not applicableUs
EstazolamTablet2 mg/1OralActavis Pharma, Inc.1997-10-01Not applicableUs
EstazolamTablet1 mg/1OralActavis Pharma, Inc.1997-10-01Not applicableUs
EstazolamTablet2 mg/1OralMayne Pharma2016-08-03Not applicableUs
EstazolamTablet1 mg/1OralMayne Pharma2016-08-03Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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

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  • Product Code
    Product Code

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

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International/Other Brands
Esilgan (Takeda) / Eurodin (Takeda) / Nuctalon (Takeda)
Categories
UNII
36S3EQV54C
CAS number
29975-16-4
Weight
Average: 294.738
Monoisotopic: 294.067224079
Chemical Formula
C16H11ClN4
InChI Key
CDCHDCWJMGXXRH-UHFFFAOYSA-N
InChI
InChI=1S/C16H11ClN4/c17-12-6-7-14-13(8-12)16(11-4-2-1-3-5-11)18-9-15-20-19-10-21(14)15/h1-8,10H,9H2
IUPAC Name
12-chloro-9-phenyl-2,4,5,8-tetraazatricyclo[8.4.0.0²,⁶]tetradeca-1(10),3,5,8,11,13-hexaene
SMILES
ClC1=CC2=C(C=C1)N1C=NN=C1CN=C2C1=CC=CC=C1

Pharmacology

Indication

For the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.

Associated Conditions
Pharmacodynamics

Estazolam, a triazolobenzodiazepine derivative, is an oral hypnotic agent with anticonvulsant, hypnotic, and muscle relaxant properties. It has been shown in some cases to be more potent than diazepam or nitrazepam.

Mechanism of action

Benzodiazepines bind nonspecifically to benzodiazepine receptors, which affects 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 GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
AGABA(A) Receptor Benzodiazepine Binding Site
ligand
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Tablets have been found to be equivalent in absorption to an orally administered solution of estazolam. In healthy subjects who received up to three times the recommended dose, peak estazolam plasma concentrations occurred within two hours after dosing (range 0.5 to 6.0 hours) and were proportional to the administered dose, suggesting linear pharmacokinetics over the dosage range tested.

Volume of distribution
Not Available
Protein binding

93% protein bound, independant of concentration.

Metabolism

Extensively metabolized in the liver. In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by cytochrome P450 3A (CYP3A).

Route of elimination

Estazolam is extensively metabolized. The elimination of the parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites that are eliminated largely in the urine both free and conjugated. Less than 5% of a 2 mg dose of estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces. Radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. After 5 days, 87% of the administered radioactivity was excreted in human urine. Less than 4% of the dose was excreted unchanged.

Half life

The range of estimates for the mean elimination half-life of estazolam varies from 10 to 24 hours.

Clearance
Not Available
Toxicity

Symptoms of overdose include confusion, depressed breathing, drowsiness and eventually coma, lack of coordination, and slurred speech.

Affected organisms
  • Humans and other mammals
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
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Estazolam is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe therapeutic efficacy of Estazolam 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 Estazolam is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Estazolam is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Estazolam is combined with 5-methoxy-N,N-dimethyltryptamine.
6-Deoxyerythronolide BThe serum concentration of Estazolam can be increased when it is combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe therapeutic efficacy of Estazolam can be decreased when used in combination with 6-O-benzylguanine.
7-DeazaguanineThe therapeutic efficacy of Estazolam can be decreased when used in combination with 7-Deazaguanine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Estazolam is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when Estazolam is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
  • Avoid alcohol.
  • Take with or without food. The absorption is unaffected by food.

References

Synthesis Reference

Hester, J.B. Jr.; U.S. Patent 3,701,782; October 31, 1972; assigned to The Upjohn Co.

General References
  1. Watanabe S, Ohta H, Sakurai Y, Takao K, Ueki S: [Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants]. Nihon Yakurigaku Zasshi. 1986 Jul;88(1):19-32. [PubMed:3758874]
  2. Oishi R, Nishibori M, Itoh Y, Saeki K: Diazepam-induced decrease in histamine turnover in mouse brain. Eur J Pharmacol. 1986 May 27;124(3):337-42. [PubMed:3089825]
  3. Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A: Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. Biol Pharm Bull. 2002 Apr;25(4):441-5. [PubMed:11995921]
External Links
Human Metabolome Database
HMDB0015346
KEGG Drug
D00311
KEGG Compound
C06981
PubChem Compound
3261
PubChem Substance
46507430
ChemSpider
3146
BindingDB
50240450
RxNav
4077
ChEBI
4858
ChEMBL
CHEMBL285674
ZINC
ZINC000000001370
Therapeutic Targets Database
DAP000930
PharmGKB
PA449502
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Estazolam
ATC Codes
N05CD04 — Estazolam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentSleep Initiation and Maintenance Disorders1
4CompletedTreatmentPrimary Insomnia / Sleep Initiation and Maintenance Disorders1
4RecruitingTreatmentRenal Dialysis / Sleep Initiation and Maintenance Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Abbott Laboratories Ltd.
  • Dispensing Solutions
  • Lake Erie Medical and Surgical Supply
  • Murfreesboro Pharmaceutical Nursing Supply
  • Par Pharmaceuticals
  • Rebel Distributors Corp.
  • Southwood Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
  • Watson Pharmaceuticals
Dosage forms
FormRouteStrength
TabletOral1 mg/1
TabletOral2 mg/1
TabletOral
Prices
Unit descriptionCostUnit
Prosom 2 mg tablet1.71USD tablet
Prosom 1 mg tablet1.53USD tablet
Estazolam 2 mg tablet0.96USD tablet
Estazolam 1 mg tablet0.86USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)228-229Hester, J.B. Jr.; U.S. Patent 3,701,782; October 31, 1972; assigned to The Upjohn Co.
water solubilityPractically insoluble (1.5 mg/L)Not Available
logP4.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0423 mg/mLALOGPS
logP1.72ALOGPS
logP2.09ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)18.4ChemAxon
pKa (Strongest Basic)4.97ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area43.07 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity94.44 m3·mol-1ChemAxon
Polarizability29.83 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9796
Caco-2 permeable+0.8427
P-glycoprotein substrateNon-substrate0.5939
P-glycoprotein inhibitor INon-inhibitor0.7883
P-glycoprotein inhibitor IIInhibitor0.7786
Renal organic cation transporterInhibitor0.7784
CYP450 2C9 substrateNon-substrate0.8367
CYP450 2D6 substrateNon-substrate0.9081
CYP450 3A4 substrateSubstrate0.674
CYP450 1A2 substrateInhibitor0.8989
CYP450 2C9 inhibitorInhibitor0.822
CYP450 2D6 inhibitorNon-inhibitor0.8586
CYP450 2C19 inhibitorInhibitor0.6571
CYP450 3A4 inhibitorNon-inhibitor0.6818
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8676
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.7126
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.0584 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9752
hERG inhibition (predictor II)Non-inhibitor0.8944
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)MSsplash10-0a4u-4590000000-dbd088d66293b3b539c3
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 1,2,4-triazolo[4,3-a][1,4]benzodiazepines. These are aromatic compounds containing a 1,4-benzodiazepine fused to and sharing a nitrogen atom with a 1,2,4-triazole ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
1,4-benzodiazepines
Direct Parent
1,2,4-triazolo[4,3-a][1,4]benzodiazepines
Alternative Parents
Benzene and substituted derivatives / Aryl chlorides / Triazoles / Heteroaromatic compounds / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organopnictogen compounds / Organochlorides / Hydrocarbon derivatives
Substituents
1,2,4-triazolo[4,3-a][1,4]benzodiazepine / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid / Azole / 1,2,4-triazole / Heteroaromatic compound / Ketimine / Propargyl-type 1,3-dipolar organic compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
triazoles, triazolobenzodiazepine (CHEBI:4858)

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. Miura M, Otani K, Ohkubo T: Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam. Xenobiotica. 2005 May;35(5):455-65. [PubMed:16012077]

Drug created on June 13, 2005 07:24 / Updated on June 12, 2020 11:41

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