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Name: Efaproxiral
Generic Names: RSR13[1], [2],[3], [4],[5]
GSJ 61[5]
JP 4[5]
KDD 86[5]
RS 4[5]
Trade Names: EfaproxynTM(Allos therapeutics Inc)[6], [7], [8], [14]
IUPAC name: 2-[4-{[(3,5-dimethylanilino)carbonyl]methyl} phenoxyl]-2-methylpropionic acid[9], [10],[11],[3], [12],[14], [31]
Molecular Weight: 363.38 for efaproxiral Sodium salt[1]
monoisotopic mass of 341.16[2], 341.4 g/mol[13]
Structure: [11], [13], [14], [31], [10]
Functional Group/
chirality is shown to affect the allosteric effector activity. Modifying the gem-dimethyl group of RSR13 with various alkyl groups reduced activity[15]
Chemical Nature: analog of bezafibrate[16]and also of clofibrate[17]
clofibric acid derivative[1]
& Indications:
Pharmcological Action-
synthetic allosteric modifier of hemoglobin[1], [18],[28]
modulator tumor hypoxia[19]
Therapeutic benefits/Indications:
The FDA granted efaproxiral orphan drug status in August 2004 as an adjunct to whole brain radiotherapy(WBRT) for the treatment of brain metastases among breast cancer patients[5]
Preclinical study-
efaproxiral is suggested to improve results of WBRT in case of breast cancer patients[20], in clinical sttings.[21],[14] also said to be promising radiosensitizer for central nervous system tumors[19]
Efaproxiral is suggested to be potential application in treatment of hypoxia, ischemia, trauma-related blood loss[16]
Efaproxiral improved myocardial recovery following hypothermic cardiopulmonary bypass in dogs in vivo[22]
Efaproxiral is suggested to have application in decreasing the effect of acute hemorrhagic hypoxemia in rats by increasing brain oxygenation[23]
RSR13 improved myocardial oxidative metabolism and contractile function in models of myocardial ischemia and also in patients with cardiopulmonary bypass. In animals, it reduced neuronal cell death following cerebral ischemia[24]
efaproxiral dose-dependently increases brain pO2 without affecting other physiological factors in rats, making it useful in circumstances where pO2 of te brain is compromised[25]
RSR13 is shown to protect adenosine triphosphates during low-flow ischemia and myocardial recovery after reperfusion in rat heart[30]
Notes: efaproxiral is prohibited in sports according to World Anti-Doping Agency(WADA)[10]
efaproxiral is developed by Allos therapeutics Inc[18]
Working concentration of efaproxiral was found to be stable at room temperature for 24 h[13]
efaproxiral impurity is a synthetic precursor to efaproxiral. It is present in trace levels(<0.1%) in efaproxiral[13]
In vivo EPR oximetry is found to be suitable for monitoring effects of efaroxiral on tumor oxygenation in a rodent model with an intracranial tumor[26], as well as in mouse model with fibrosarcoma[27]
BOLD(Blood Oxygen level dependent)-MRI has also been employed to monitor tumor physiology change after efaproxiral administration in mice transplanted with fibrosarcoma[27]
patents for methods of allosterically modifying haemoglobin with efaproxiral and the binding site of efaproxiral, efaproxiral in certain indications including cancer, ischaemia and hypoxia are own by Allos therapeutics Inc. In addition to the licensed patents from CIT, Allos exclusively owns two patent families with pending applications directed to a formulation of efaproxiral and to methods of its use in BLOD MRI (blood oxygenation level-dependent magnetic resonance imaging) applications[5], and other patents also exists for other variety of applications of RSR13[29]
Breathing a high oxygent content atmosphere enhnaces the tumor oxygenating activity of RSR13[31]
A chiral analogue, (-)- (1R,2R)-1-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylcyclopentanecarboxylic acid, exhibited greater in vitro activity in hemoglobin solutions than RSR13, and also found to be equipotent with RSR13 in whole blood,[15]
The 2-methylcyclopentyl derivative of RSR13 was the most potent allosteric effector[15]
1. Suh JH, Efaproxiral:a novel radiation sensitizer. Expert Opin Investig Drugs. 2004;13(5):543-50.
2. Ventura R et al, High-throughput and sensitive screening by ultra-performance liquid chromatography tandem mass spectrometry of diuretics and other doping agents. Eur J Mass Spectrom (Chichester, Eng). 2008;14(3):191-200.
3. Breidbach A, Catlin DH, RSR13, a potential athletic performance enhancement agent: detection in urine by gas chromatography/mass spectrometry. Rapid Commun Mass Spectrom. 2001;15(24):2379-82.
4. Hardy LW, Malikayil A, The impact of structure-guided drug design on clinical agents. www.currentdrugdiscovery.com 2003:15-20.
5. Efaproxiral: GSJ 61, JP 4, KDD 86, RS 4, RSR 13. Drugs R D. 2005;6(3):178-85.
6. Suh JH et al, Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol. 2006;24(1):106-14.
7. Stea B et al, Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: Determinants of response and its prognostic value for subsequent survival. Int J Radiat Oncol Biol Phys. 2006;64(4):1023-30
8. Engel RH, Kaklamani VG, Role of efaproxiral in metastatic brain tumors. Expert Rev Anticancer Ther. 2006;6(4):477-85.
9. Jiménez C, Ventura R, Segura J, Detection in urine of efaproxiral (RSR13), a potential doping agent, by a routine screening procedure based on methylation followed by gas chromatography/mass spectrometry. Analytica Chimica Acta. 2004;505:227–229.
10. Thevis M, Krug O, Schänzer W, Mass spectrometric characterization of efaproxiral (RSR13) and its implementation into doping controls using liquid chromatography-atmospheric pressure ionization-tandem mass spectrometry. J Mass Spectrom. 2006;41(3):332-8.
11. Youssef AM et al, Synthesis and X-ray studies of chiral allosteric modifiers of hemoglobin. J Med Chem. 2002;45(6):1184-95.
12. Kleinberg L et al, 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. J Clin Oncol. 2002;20(14):3149-55.
13. Yi R et al, Detection of efaproxiral (RSR13) and its metabolites in equine by liquid chromatography tandem mass spectrometry. J Mass Spectrom. 2014;49(1):57-67.
14. Charpentier MM, Efaproxiral: A radiation enhancer used in brain metastases from breast cancer. Ann Pharmacother. 2005;39(12):2038-2045.
15. Phelps Grella M et al, Synthesis and structure-activity relationships of chiral allosteric modifiers of hemoglobin. J. Med. Chem. 2000; 43(25): 4726-4737.
16. Safo MK et al, High-resolution crystal structure of deoxy hemoglobin complexed with a potent allosteric effector. Protein Sci. 2001;10(5):951-7.
17. Wahr JA et al, Allosteric modification of oxygen delivery by hemoglobin. Anesth Analg. 2001;92(3):615-20.
18. Kolman A, Efaproxiral (Allos Therapeutics). IDrugs. 2003;6(8):795-801.
19. Mehta MP, Suh JH, Novel radiosensitizers for tumors of the central nervous system. Curr Opin Investig Drugs. 2004;5(12):1284-91.
20. Sneed PK, Efaproxiral: Should We Hold Our Breath? J Clin Oncol. 2006;24(1):13-5.
21. Shaw E et al, Pharmacokinetics (PK) of RSR13 (efaproxiral) predict survival in patients with brain metastases randomized to receive whole brain radiation therapy (WBRT) with or without RSR13 (REACH RT-009). J Clin Oncol (Meeting Abstracts) 2004;22(14_suppl): 1561.
22. Kilgore KS et al, RSR13, a synthetic allosteric modifier of hemoglobin, improves myocardial recovery following hypothermic cardiopulmonary bypass. Circulation.1999; 100:(suppl II):II-351–II-356.
23. Miyake M et al, The effect of RSR13, a synthetic allosteric modifier of hemoglobin, on brain tissue pO2 (measured by EPR oximetry) following severe hemorrhagic shock in rats. Adv Exp Med Biol. 2003;530:319-29.
24. Steffen RP et al, Allosteric modification of hemoglobin by RSR13 as a therapeutic strategy. Adv Exp Med Biol. 2003;530:249-59.
25. Grinberg OY et al, The dose-dependent effect of RSR13, a synthetic allosteric modifier of hemoglobin, on physiological parameters and brain tissue oxygenation in rats. Adv Exp Med Biol. 2003;530:287-96.
26. Hou H et al, Increased oxygenation of intracranial tumors by efaproxyn (efaproxiral), an allosteric hemoglobin modifier: In vivo EPR oximetry study. Int J Radiat Oncol Biol Phys. 2005;61(5):1503-9.
27. Hou H et al, Effect of RSR13, an allosteric hemoglobin modifier, on oxygenation in murine tumors: an in vivo electron paramagnetic resonance oximetry and bold MRI study. Int J Radiat Oncol Biol Phys. 2004;59(3):834-43.
28. Randad RS et al, Allosteric modifiers of hemoglobin. 1. Design, synthesis, testing, and structure-allosteric activity relationship of novel hemoglobin oxygen affinity decreasing agents. J Med Chem. 1991;34(2):752-7.
29. 1.Method for lowering oxygen affinity of hemoglobin in redcell suspensions, in whole blood and in vivo US 5661182 A, 1997.
2. Use of hemoglobin effectors to increase the bioavailability of therapeutic gases US 20130266668 A1
3. Perinatal treatment of a fetus to avoid oxygen deprivation US 5827888 A
30. Woods JA et al, Right-shifting the oxyhemoglobin dissociation curve with RSR13: effects on high-energy phosphates and myocardial recovery after low-flow ischemia. J Cardiovasc Pharmacol. 1998;31(3):359-63.
31. Teicher BA et al, RSR13: Effects on tumor oxygenation and response to therapy. Drug Development Research 1996;38(1):1-11.