ETANIDAZOLE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C7H10N4O4
Molecular Weight	214.1787
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OCCNC(=O)CN1C=CN=C1[N+]([O-])=O

InChI

InChIKey=WCDWBPCFGJXFJZ-UHFFFAOYSA-N

InChI=1S/C7H10N4O4/c12-4-2-8-6(13)5-10-3-1-9-7(10)11(14)15/h1,3,12H,2,4-5H2,(H,8,13)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8398704 | https://adisinsight.springer.com/drugs/800000828

Etanidazole (also known as Radinyl) is a 2-nitroimidazole with radiosensitizing properties. Etanidazole exerts its therapeutic action by depleting glutathione and inhibiting glutathione S-transferase, thus enhancing the anticancer effects of radiation therapy. Etanidazole was tested in Phase III clinical trials in patients with advanced head and neck cancer, however, its development was stopped. A fluorinated etanidazole (EF5) may also be useful as an imaging agent for identification of hypoxic, drug-resistant regions of primary tumors and metastases.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Glutathione-S-transferase 2 Target ID: Glutathione-S-transferase Sources: https://www.ncbi.nlm.nih.gov/pubmed/8398704	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Advanced head and neck cancer 2 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9308928	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
287 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2522918	2 g/m² single, intravenous dose: 2 g/m² route of administration: Intravenous experiment type: SINGLE co-administered:		ETANIDAZOLE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
2.55 mM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1826961	4 g/m² single, intravenous dose: 4 g/m² route of administration: Intravenous experiment type: SINGLE co-administered:		ETANIDAZOLE serum	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
5.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2522918	2 g/m² single, intravenous dose: 2 g/m² route of administration: Intravenous experiment type: SINGLE co-administered:		ETANIDAZOLE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP1B3 706 CYP1A2 1524 OATP1B1 788	P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP2C19 1553	activator 214 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/899#sid=11112677	no [Activation 5.0119 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/410#sid=11112677	no
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/883#sid=11112677	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/891#sid=11112677	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/885#sid=11112677	no
OATP1B1 803	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23571415/	yes [Inhibition 10 uM]
OATP1B3 715	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23571415/	yes [Inhibition 10 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=144204150	no

Sourcing

Vendor/Aggregator	ID	URL
AKOS	AKOS028109842	http://akoscompounds.de/catalogue/AKosSamplesiSSretrieval.php?GUID=4e4caa52-3dca-4da0-b75a-caeae59e1096&IDNUMBERS=AKOS028109842
BOC Sciences	22668-01-5	http://www.bocsci.com/description.asp?cas=22668-01-5
Compound Cloud	3276
Enamine	BBV-45084632	http://www.enaminestore.com/catalog/BBV-45084632
Hairui	HR144737	http://www.hairuichem.com/en/product/search.do?q=HR144737
Lab Network	LN01310035	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01310035
MuseChem	R043807	https://www.musechem.com/product/R043807.html
NCI Plated 2007	301467
eMolecules	33507364	https://orderbb.emolecules.com/search/#?query=33507364

PubMed

Title	Date	PubMed
Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide.	1993 Oct	8398704
Pneumocystis carinii is resistant to imidazole antifungal agents.	1994 Aug	7986021
Combined-modality therapy of esophageal cancer with radiotherapy, etanidazole, and cisplatin-fluorouracil, with or without surgery: neurotoxicity, other toxicities and outcome.	1994 Jun 15	8005812
Hypoxia in radiation-induced blood-spinal cord barrier breakdown.	2001 Apr 15	11309291
Validation of the RTOG recursive partitioning classification for head and neck tumors.	2001 Aug	11443750
Effects of radiation on tumor intravascular oxygenation, vascular configuration, development of hypoxia, and clonogenic survival.	2001 Feb	11175672
Differential effects of buthionine sulphoximine in hypoxic and non-hypoxic regions of human cervical carcinoma xenografts.	2001 Jul	11410306
Green fluorescent protein is a suitable reporter of tumor hypoxia despite an oxygen requirement for chromophore formation.	2001 Nov-Dec	11774035
Characterization of the effects of antiangiogenic agents on tumor pathophysiology.	2001 Oct	11586095
Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles.	2001 Sep	11592338
Combined prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus arteriosus in the premature newborn baboon.	2001 Sep	11518824
Intravascular HBO(2) saturations, perfusion and hypoxia in spontaneous and transplanted tumor models.	2001 Sep 1	11477580
Hypoxia and etanidazole alter radiation-induced apoptosis in HL60 cells but not in MOLT-4 cells.	2002 Apr	12020438
Vasa vasorum hypoperfusion is responsible for medial hypoxia and anatomic remodeling in the newborn lamb ductus arteriosus.	2002 Feb	11809919
Sustained release of etanidazole from spray dried microspheres prepared by non-halogenated solvents.	2002 Jun 17	12044566
Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1.	2002 Oct 15	12388599
In vivo colocalization of 2-nitroimidazole EF5 fluorescence intensity and electron paramagnetic resonance oximetry in mouse tumors.	2003 Apr	12758240
Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5.	2003 Feb	12552344
Sustained release system for highly water-soluble radiosensitizer drug etanidazole: irradiation and degradation studies.	2003 May	12615488
Hypoxia and Photofrin uptake in the intraperitoneal carcinomatosis and sarcomatosis of photodynamic therapy patients.	2004 Jul 15	15269134
In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography.	2004 Jun 1	15150578
Quality of life of men treated with brachytherapies for prostate cancer.	2004 Jun 15	15198803
In vitro activity of Etanidazole against the protozoan parasite Trypanosoma cruzi.	2004 Mar	15250482
Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma.	2004 Mar 15	15026343
Role of myocardial hypoxia in the remodeling of the embryonic avian cardiac outflow tract.	2004 Mar 15	15013795
New methods for direct delivery of chemotherapy for treating brain tumors.	2006 Dec	17940624
Oxygen levels in normal and previously irradiated human skin as assessed by EF5 binding.	2006 Dec	16810299
Detection of tumour hypoxia: comparison between EF5 adducts and [18F]EF3 uptake on an individual mouse tumour basis.	2006 May	16523307
Identifying and targeting hypoxia in head and neck cancer: a brief overview of current approaches.	2007	17848296
Radiosensitization by the combination of SR-2508 and paclitaxel in hypoxic human tumor cells in vitro.	2007 May	17420623
A phase I-B trial of the radiosensitizer: etanidazole (SR-2508) with radiosurgery for the treatment of recurrent previously irradiated primary brain tumors or brain metastases (RTOG Study 95-02).	2008 Apr	18342381
Imaging and analytical methods as applied to the evaluation of vasculature and hypoxia in human brain tumors.	2008 Dec	19138031
18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer.	2008 Dec	18997048
Regulation of cell survival and death signals induced by oxidative stress.	2008 Sep	18818753
Inhibitor of DNA binding/differentiation 2 induced by hypoxia promotes synovial fibroblast-dependent osteoclastogenesis.	2009 Dec	19950294
Immunohistochemical detection of changes in tumor hypoxia.	2009 Mar 15	19251089
Atrasentan (ABT-627) enhances perfusion and reduces hypoxia in a human tumor xenograft model.	2009 Oct	19717985
A fast radiotherapy paradigm for anal cancer with volumetric modulated arc therapy (VMAT).	2009 Oct 25	19852856

Patents

Sample Use Guides

In Vivo Use Guide

Etanidazole is given at a dose of 2.0 g/m(2), three times per week for 5.5 weeks in 17 doses up to a total dose of 34 g/m(2). The drug is dissolved in saline and infused i.v., over 10 to 15 min. Radiotherapy is to begin 30 to 60 min after the start of the Etanidazole infusion.

Route of Administration: Intravenous

In Vitro Use Guide

Human leukemia cell lines HL60 and MOLT-4 were treated with 10 mM etanidazole by incubating cells (10(6) ml(-1)) in growth medium at 37 Celsius for 1 h before X-irradiation (15 Gy). The treatment of cells with etanidazole enhanced X-ray-induced apoptosis and the ladder-like DNA fragmentation under the hypoxic conditions.

Name

Type

Language

ETANIDAZOLE

Official Name

English

ETANIDAZOLE [MART.]

Common Name

English

N-(2-Hydroxyethyl)-2-nitroimidazole-1-acetamide

Systematic Name

English

NSC-301467

Code

English

etanidazole [INN]

Common Name

English

RADINYL

Brand Name

English

SR 2508

Code

English

SR-2508

Code

English

ETANIDAZOLE [USAN]

Common Name

English

ETANIDAZOLE [MI]

Common Name

English

1H-IMIDAZOLE-1-ACETAMIDE, N-(2-HYDROXYETHYL)-2-NITRO-

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C798