EFAPROXIRAL SODIUM

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H22NO4.Na
Molecular Weight	363.3827
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Na+].CC1=CC(NC(=O)CC2=CC=C(OC(C)(C)C([O-])=O)C=C2)=CC(C)=C1

InChI

InChIKey=SWDPIHPGORBMFR-UHFFFAOYSA-M

InChI=1S/C20H23NO4.Na/c1-13-9-14(2)11-16(10-13)21-18(22)12-15-5-7-17(8-6-15)25-20(3,4)19(23)24;/h5-11H,12H2,1-4H3,(H,21,22)(H,23,24);/q;+1/p-1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15869322 | http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B1_03_Allos-RSR13.htm#_Toc68333919
Curator's Comment: Description was created based on several sources, including: http://adisinsight.springer.com/drugs/800008565

Efaproxiral is a synthetic, small molecule, radiation-sensitising agent being developed by Allos Therapeutics primarily for the treatment of cancer. It works by binding and allosterically stabilising deoxyhaemoglobin in hypoxic regions of tumour tissue. This increases oxygen uptake of the tumour tissue and restores its sensitivity to radiation therapy, making therapy potentially more successful. But no benefit was seen for efaproxiral in phase III clinical trials. The only serious adverse effect detected was hypoxaemia. Efaproxiral is explicitly excluded from the 2012 World Anti-Doping Agency list of Prohibited Substances and is explicitly included in the Prohibited Methods section M1 as a forbidden procedure to alter the oxygen-haemoglobin dissociation curve in order to allosterically modify haemoglobin.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Hemoglobin HbA 4 Target ID: CHEMBL2095168 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15869322 \| http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B1_03_Allos-RSR13.htm#_Toc68333919	Modulator 828

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT00004202	Primary	Phase II 1132	Unknown Approved Use Unknown
Glioblastoma multiforme 30 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12118029	Primary	Phase II 1132	Unknown Approved Use Unknown
Ischemic heart disease 7 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9535987	Primary	Preclinical	Unknown Approved Use Unknown
Breast cancer metastases 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00083304 http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B1_03_Allos-RSR13.htm#_Toc68333919	Primary	Phase III 656	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
RSR13, a potential athletic performance enhancement agent: detection in urine by gas chromatography/mass spectrometry.	2001	11746905
Allosteric modification of oxygen delivery by hemoglobin.	2001 Mar	11226087
A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics.	2001 Mar 15	11240256
High-resolution crystal structure of deoxy hemoglobin complexed with a potent allosteric effector.	2001 May	11316875
Effects of enhanced oxygen release from hemoglobin by RSR13 in an acute renal failure model.	2001 Oct	11576354
Enhancement of tumor oxygenation and radiation response by the allosteric effector of hemoglobin, RSR13.	2001 Sep	11500138
Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study.	2002 Jul 15	12118029
Pharmacological correction of hypothermic P(50) shift does not alter outcome from focal cerebral ischemia in rats.	2002 May	11959653
The dose-dependent effect of RSR13, a synthetic allosteric modifier of hemoglobin, on physiological parameters and brain tissue oxygenation in rats.	2003	14562725
Allosteric modification of hemoglobin by RSR13 as a therapeutic strategy.	2003	14562722
Efaproxiral: a novel radiation sensitiser.	2004 May	15155129
Modeling of the response of ptO2 in rat brain to changes in physiological parameters.	2005	16594142
Effects of a pharmacologically-induced shift of hemoglobin-oxygen dissociation on myocardial energetics during ischemia in patients with coronary artery disease.	2005	16136855
Efaproxiral: GSJ 61, JP 4, KDD 86, RS 4, RSR 13.	2005	15869322
Increased oxygenation of intracranial tumors by efaproxyn (efaproxiral), an allosteric hemoglobin modifier: In vivo EPR oximetry study.	2005 Apr 1	15817356
Efaproxiral: a radiation enhancer used in brain metastases from breast cancer.	2005 Dec	16249270
R-state hemoglobin bound to heterotropic effectors: models of the DPG, IHP and RSR13 binding sites.	2005 Jan 31	15670819
Hit to Lead Success Stories--IBC Conference: Effective chemistry strategies for reducing attrition rates and speeding lead compounds into the pipeline. 31 January-1 February 2005, San Diego, CA, USA.	2005 Mar	15772889
Phase II multicenter study of induction chemotherapy followed by concurrent efaproxiral (RSR13) and thoracic radiotherapy for patients with locally advanced non-small-cell lung cancer.	2005 Sep 1	16135463
Cerebral metastases--a therapeutic update.	2006 Aug	16932601
New hope for old drug in patients with brain metastases.	2006 Feb	16468181
Radiation sensitization with redox modulators: a promising approach.	2006 Feb 1	16414370
Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases.	2006 Jan 1	16314619
Efaproxiral: should we hold our breath?	2006 Jan 1	16314614
Integration of chemotherapy into current treatment strategies for brain metastases from solid tumors.	2006 Jun 27	16800900
Efaproxiral (RSR13) plus oxygen breathing increases the therapeutic ratio of carboplatin in EMT6 mouse mammary tumors.	2006 Mar	16514179
Mass spectrometric characterization of efaproxiral (RSR13) and its implementation into doping controls using liquid chromatography-atmospheric pressure ionization-tandem mass spectrometry.	2006 Mar	16421876
Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: Determinants of response and its prognostic value for subsequent survival.	2006 Mar 15	16446056
Current therapeutic approaches in patients with brain metastases.	2006 Nov	17032560
Using exposure-response and biomarkers to streamline early drug development.	2007	17117714
The effects of Efaproxyn (efaproxiral) on subcutaneous RIF-1 tumor oxygenation and enhancement of radiotherapy-mediated inhibition of tumor growth in mice.	2007 Aug	17638413
Improved survival, quality of life, and quality-adjusted survival in breast cancer patients treated with efaproxiral (Efaproxyn) plus whole-brain radiation therapy for brain metastases.	2007 Dec	18091051
Whole brain radiotherapy for brain metastases from breast cancer: estimation of survival using two stratification systems.	2007 Mar 26	17386108
Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failure.	2008 Aug 26	18718428
Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxiral.	2008 Mar 7	18292903
Quality of life in brain metastases radiation trials: a literature review.	2008 Oct	19008990
Neuropsychological testing and biomarkers in the management of brain metastases.	2008 Sep 17	18798997
Role of palliative radiotherapy in brain metastases.	2009 Jan	20606860
Whole brain radiotherapy with radiosensitizer for brain metastases.	2009 Jan 6	19126230
The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics.	2010 Jan	19957013
Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study.	2010 Mar	19767314

Patents

Sample Use Guides

In Vivo Use Guide

Efaproxiral was administered intravenously via a central venous access device over 30 minutes; the infusion was completed no more than 30 minutes before whole-brain radiation therapy. The intended daily dose of efaproxiral was 75 or 100 mg/kg.

Route of Administration: Intravenous

In Vitro Use Guide

EMT6 cells in exponentially growing cell cultures were treated with 300 mg/ml of RSR13 (Efaproxiral), with radiation, or with RSR13 (Efaproxiral) plus irradiation under either aerobic or hypoxic conditions (7.5 Gy for aerobic cultures and 20 Gy for hypoxic cultures). The survival of irradiated EMT6 cells was the same whether cells were irradiated in the presence or in the absence of RSR13 (Efaproxiral).

Name

Type

Language

EFAPROXIRAL SODIUM

Official Name

English

RSR13 SODIUM

Code

English

2-[4-[2-[(3,5-Dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid monosodium salt

Common Name

English

EFAPROXIRAL SODIUM [USAN]

Common Name

English

2-(4-(((3,5-DIMETHYLANILINO)CARBONYL)METHYL)-PHENOXY)-2-METHYLPROPIONIC ACID SODIUM

Systematic Name

English

EFAPROXIRAL SODIUM [MART.]

Common Name

English

RSR-13 SODIUM

Code

English

PROPANOIC ACID, 2-(4-(2-((3,5-DIMETHYLPHENYL)AMINO)-2-OXOETHYL)PHENOXY)-2-METHYL-, MONOSODIUM SALT

Common Name

English

Efaproxiral sodium [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C798