| 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/chemical constitution: |
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]
|
| Actions & 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]
|
| Derivatives/analogues: |
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]
|
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