Efaproxiral

Last updated
Efaproxiral
Efaproxiral.png
Clinical data
ATC code
Pharmacokinetic data
Elimination half-life 1 hr
Identifiers
  • 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H23NO4
Molar mass 341.407 g·mol−1
3D model (JSmol)
  • Cc1cc(cc(c1)NC(=O)Cc2ccc(cc2)OC(C)(C)C(=O)O)C
  • InChI=1S/C20H23NO4/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) X mark.svgN
  • Key:BNFRJXLZYUTIII-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Efaproxiral (INN) is an analogue of bezafibrate [a lipid-lowering agent], developed for the treatment of depression, traumatic brain injury, ischemia, stroke, myocardial infarction, diabetes, hypoxia, sickle cell disease, hypercholesterolemia and as a radio sensitiser. [1] [2] [3]

The chemical is a derivative of propanoic acid. One use for efaproxiral is to increase the efficacy of certain chemotherapy drugs which have reduced efficacy against hypoxic tumours, and can thus be made more effective by increased offloading of oxygen into the tumour tissues. [4] [5] [6] No benefit was seen for efaproxiral in phase III clinical trials. [7] The increased oxygenation of tissues could theoretically also produce enhanced exercise capacity in feline, rat and canine models for approximately 100 min. immediately after a high dosage 45 min. intravenous infusion. [8]

This has led World Anti-Doping Agency to categorise efaproxiral under a prohibited method to artificially enhance the uptake, transport or delivery of oxygen. [9] There is no existing evidence that efaproxiral can effectively enhance performance in humans. [10] Efaproxiral can be absorbed via transdermal, rectal, inhalation and gastrointestinal routes, though not at plasma concentrations great enough to alter the oxygen-haemoglobin dissociation curve. [11]

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. [12]

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References

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  2. US 5731454,Abraham DJ, Joshi G, Randad R, Panikker J,"Allosteric modifiers of hemoglobin useful for decreasing oxygen affinity and preserving oxygen carrying capability of stored blood",issued 24 March 1998, assigned to Virginia Commonwealth University (Richmond, VA).
  3. Kunert MP, Liard JF, Abraham DJ (August 1996). "RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats". The American Journal of Physiology. 271 (2 Pt 2): H602–H613. doi:10.1152/ajpheart.1996.271.2.H602. PMID   8770102.
  4. Donnelly ET, Liu Y, Rockwell S (March 2006). "Efaproxiral (RSR13) plus oxygen breathing increases the therapeutic ratio of carboplatin in EMT6 mouse mammary tumors". Experimental Biology and Medicine. 231 (3): 317–321. doi:10.1177/153537020623100312. PMID   16514179. S2CID   19475480.
  5. Engel RH, Kaklamani VG (April 2006). "Role of efaproxiral in metastatic brain tumors". Expert Review of Anticancer Therapy. 6 (4): 477–485. doi:10.1586/14737140.6.4.477. PMID   16613536. S2CID   3142753.
  6. Scott C, Suh J, Stea B, Nabid A, Hackman J (December 2007). "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". American Journal of Clinical Oncology. 30 (6): 580–587. doi:10.1097/COC.0b013e3180653c0d. PMID   18091051. S2CID   42750048.
  7. "FDA Advisory Committee Does Not Recommend Approval of RSR13 as Adjunctive Therapy for the Treatment of Brain Metastases Originating from Breast Cancer". Allos Therapeutics, Inc. May 2004 via Drugs.com.
  8. Watanabe T, Takeda T, Omiya S, Hikoso S, Yamaguchi O, Nakano Y, et al. (August 2008). "Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failure". Journal of the American College of Cardiology. 52 (9): 779–786. doi: 10.1016/j.jacc.2008.06.003 . PMID   18718428.
  9. "The 2009 Prohibited List" (PDF). World Anti Dopting Agency (WADA). 24 August 2011. Archived from the original (PDF) on 2009-02-03.
  10. Nóbrega AC (Feb 2002). "RSR13 e modificação alostérica da afinidade hemoglobina-oxigênio: abuso entre atletas" [RSR13 and allosteric change in the hemoglobin-oxygen Afinity[sic]]. Journal of Sports Medicine (in Portuguese). 8: 26–29. doi:10.1590/S1517-86922002000100005. ISSN   1517-8692.
  11. Campanini B, Raboni M (January 2003). "Oxygen Delivery by Allosteric Effectors of Hemoglobin, Blood Substitutes, and Plasma Expanders". Burger's Medicinal Chemistry, Drug Discovery and Development. pp. 385–441. doi:10.1002/0471266949.bmc048. ISBN   978-0471266945.
  12. "The Prohibited List 2012" (PDF). World Anti Dopting Agency (WADA). 24 August 2011. Archived from the original (PDF) on 2012-05-13. Retrieved 2012-05-10.