efaproxiral

{{short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 387464773

| IUPAC_name = 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid

| image = Efaproxiral.png

| tradename =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU =

| legal_CA =

| legal_US =

| legal_status =

| routes_of_administration =

| bioavailability =

| protein_bound =

| elimination_half-life = 1 hr

| excretion =

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 131179-95-8

| ATC_prefix = L01

| ATC_suffix = XD06

| ATC_supplemental =

| PubChem = 122335

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank =

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = J81E81G364

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 18901

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 109085

| chemical_formula =

| C=20 | H=23 | N=1 | O=4

| smiles = Cc1cc(cc(c1)NC(=O)Cc2ccc(cc2)OC(C)(C)C(=O)O)C

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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)

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = BNFRJXLZYUTIII-UHFFFAOYSA-N

}}

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.{{cite book | vauthors = Farace E, Melikyan Z |chapter= Cognitive Dysfunction, Mood Disorders, and Fatigue | title = Cancer Neurology in Clinical Practice |year=2008 |pages=242–248 |doi= 10.1007/978-1-59745-412-4_7 |isbn=978-1-58829-983-3 }}{{Cite patent | country = US | number = 5731454| url=http://www.freepatentsonline.com/5731454.html | title=Allosteric modifiers of hemoglobin useful for decreasing oxygen affinity and preserving oxygen carrying capability of stored blood | inventor = Abraham DJ, Joshi G, Randad R, Panikker J | assign1 = Virginia Commonwealth University (Richmond, VA) | gdate = 24 March 1998 | postscript = . }}{{cite journal | vauthors = Kunert MP, Liard JF, Abraham DJ | title = RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats | journal = The American Journal of Physiology | volume = 271 | issue = 2 Pt 2 | pages = H602–H613 | date = August 1996 | pmid = 8770102 | doi = 10.1152/ajpheart.1996.271.2.H602 }}

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.{{cite journal | vauthors = Donnelly ET, Liu Y, Rockwell S | title = Efaproxiral (RSR13) plus oxygen breathing increases the therapeutic ratio of carboplatin in EMT6 mouse mammary tumors | journal = Experimental Biology and Medicine | volume = 231 | issue = 3 | pages = 317–321 | date = March 2006 | pmid = 16514179 | doi = 10.1177/153537020623100312 | s2cid = 19475480 }}{{cite journal | vauthors = Engel RH, Kaklamani VG | title = Role of efaproxiral in metastatic brain tumors | journal = Expert Review of Anticancer Therapy | volume = 6 | issue = 4 | pages = 477–485 | date = April 2006 | pmid = 16613536 | doi = 10.1586/14737140.6.4.477 | s2cid = 3142753 }}{{cite journal | vauthors = Scott C, Suh J, Stea B, Nabid A, Hackman J | title = 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 | journal = American Journal of Clinical Oncology | volume = 30 | issue = 6 | pages = 580–587 | date = December 2007 | pmid = 18091051 | doi = 10.1097/COC.0b013e3180653c0d | s2cid = 42750048 }} No benefit was seen for efaproxiral in phase III clinical trials.{{Cite web | url=https://www.drugs.com/nda/rsr13_040504.html | title=FDA Advisory Committee Does Not Recommend Approval of RSR13 as Adjunctive Therapy for the Treatment of Brain Metastases Originating from Breast Cancer | date = May 2004 | via = Drugs.com | work = Allos Therapeutics, Inc. }} 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.{{cite journal | vauthors = Watanabe T, Takeda T, Omiya S, Hikoso S, Yamaguchi O, Nakano Y, Higuchi Y, Nakai A, Abe Y, Aki-Jin Y, Taniike M, Mizote I, Matsumura Y, Shimizu T, Nishida K, Imai K, Hori M, Shirasawa T, Otsu K | display-authors = 6 | title = Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failure | journal = Journal of the American College of Cardiology | volume = 52 | issue = 9 | pages = 779–786 | date = August 2008 | pmid = 18718428 | doi = 10.1016/j.jacc.2008.06.003 | name-list-style = vanc | doi-access = free }}

This has led World Anti-Doping Agency to categorise efaproxiral under a prohibited method to artificially enhance the uptake, transport or delivery of oxygen.{{cite web | url = http://www.wada-ama.org/rtecontent/document/2009_Prohibited_List_ENG_Final_20_Sept_08.pdf | work = World Anti Dopting Agency (WADA) | title = The 2009 Prohibited List | date = 24 August 2011 | archive-url = https://web.archive.org/web/20090203030039/http://www.wada-ama.org/rtecontent/document/2009_Prohibited_List_ENG_Final_20_Sept_08.pdf | archive-date=2009-02-03 }} There is no existing evidence that efaproxiral can effectively enhance performance in humans.{{cite journal | vauthors = Nóbrega AC |title=RSR13 e modificação alostérica da afinidade hemoglobina-oxigênio: abuso entre atletas|trans-title=RSR13 and allosteric change in the hemoglobin-oxygen {{sic|nolink=y|reason=error in source|Afinity}} |journal=Journal of Sports Medicine|volume=8 |date=Feb 2002 |pages=26–29 |doi=10.1590/S1517-86922002000100005 |issn= 1517-8692 |url=http://www.scielo.br/scielo.php?pid=S1517-86922002000100005&script=sci_arttext|language=pt|doi-access=free }} 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.{{cite book | vauthors = Campanini B, Raboni M |chapter=Oxygen Delivery by Allosteric Effectors of Hemoglobin, Blood Substitutes, and Plasma Expanders |title=Burger's Medicinal Chemistry, Drug Discovery and Development |date=January 2003 |pages=385–441 |doi= 10.1002/0471266949.bmc048 |isbn=978-0471266945 }}

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.{{cite web |url=http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/2012/WADA_Prohibited_List_2012_EN.pdf |title = The Prohibited List 2012 | work = World Anti Dopting Agency (WADA) | date = 24 August 2011 |access-date=2012-05-10 |url-status=dead |archive-url=https://web.archive.org/web/20120513020202/http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/2012/WADA_Prohibited_List_2012_EN.pdf |archive-date=2012-05-13 }}