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Revision as of 19:44, 16 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456621758 of page Acadesine for the Chem/Drugbox validation project (updated: 'CAS_number').		Latest revision as of 22:01, 6 March 2024 edit Maxim Masiutin (talk | contribs)Extended confirmed users, IP block exemptions, Pending changes reviewers31,052 edits Removed parameters. | Use this tool. Report bugs. | #UCB_Gadget
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			{{Short description|Chemical compound}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{cs1 config|name-list-style=vanc}}
			{{distinguish|5-aminoimidazole-4-carboxamide ribotide}}
	{{Drugbox		{{Drugbox
			| Verifiedfields = changed
	| verifiedrevid = 452608490		| verifiedrevid = 477237572
	| IUPAC_name = 5-amino-1--1''H''-imidazole-4-carboxamide		| IUPAC_name = 5-amino-1--1''H''-imidazole-4-carboxamide
	| image = Acadesine structure.png		| image = Acadesine structure.svg
	<!--Clinical data-->		<!--Clinical data-->
	| tradename =		| tradename =
	| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->		| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
	| pregnancy_US = <!-- A / B / C / D / X -->		| pregnancy_US = <!-- A / B / C / D / X -->
	| pregnancy_category =		| pregnancy_category =
	| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->		| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
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	| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->		| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
	| legal_status =		| legal_status =
	| routes_of_administration =		| routes_of_administration =
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
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	| metabolism =		| metabolism =
	| elimination_half-life =		| elimination_half-life =
	| excretion =		| excretion =
	<!--Identifiers-->		<!--Identifiers-->
			| IUPHAR_ligand = 5133
	| CAS_number_Ref = {{cascite|correct|??}}		| CAS_number_Ref = {{cascite|changed|??}}
	| CAS_number = <!-- blanked - oldvalue: 2627-69-2 -->		| CAS_number = 2627-69-2
	| ATC_prefix = C01		| ATC_prefix = C01
	| ATC_suffix = EB13		| ATC_suffix = EB13
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	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank =		| DrugBank =
			| ChEBI_Ref = {{ebicite|changed|EBI}}
			| ChEBI = 28498
			| ChEMBL_Ref = {{ebicite|changed|EBI}}
			| ChEMBL = 1551724
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 16560		| ChemSpiderID = 16560
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	| chemical_formula =		| chemical_formula =
	| C=9 | H=14 | N=4 | O=5		| C=9 | H=14 | N=4 | O=5
	| molecular_weight = 258.231 g/mol
	| smiles = O=C(c1ncn(c1N)2O((O)2O)CO)N		| smiles = O=C(c1ncn(c1N)2O((O)2O)CO)N
	| InChI = 1/C9H14N4O5/c10-7-4(8(11)17)12-2-13(7)9-6(16)5(15)3(1-14)18-9/h2-3,5-6,9,14-16H,1,10H2,(H2,11,17)/t3-,5-,6-,9-/m1/s1
	| InChIKey = RTRQQBHATOEIAF-UUOKFMHZBE
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C9H14N4O5/c10-7-4(8(11)17)12-2-13(7)9-6(16)5(15)3(1-14)18-9/h2-3,5-6,9,14-16H,1,10H2,(H2,11,17)/t3-,5-,6-,9-/m1/s1		| StdInChI = 1S/C9H14N4O5/c10-7-4(8(11)17)12-2-13(7)9-6(16)5(15)3(1-14)18-9/h2-3,5-6,9,14-16H,1,10H2,(H2,11,17)/t3-,5-,6-,9-/m1/s1
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	| StdInChIKey = RTRQQBHATOEIAF-UUOKFMHZSA-N		| StdInChIKey = RTRQQBHATOEIAF-UUOKFMHZSA-N
	}}		}}
			'''Acadesine''' (]), also known as '''5-aminoimidazole-4-carboxamide-1-β-<small>D</small>-ribofuranoside''', '''AICA-riboside''', and '''AICAR''', is an ] activator<ref>{{cite journal | vauthors = Favero CB, Mandell JW | title = A pharmacological activator of AMP-activated protein kinase (AMPK) induces astrocyte stellation | journal = Brain Research | volume = 1168 | pages = 1–10 | date = September 2007 | pmid = 17706943 | pmc = 2000700 | doi = 10.1016/j.brainres.2007.06.087 }}</ref> which is used for the treatment of ]<ref>{{cite journal | vauthors = Cronstein BN, Kamen BA | title = 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICA-riboside) as a targeting agent for therapy of patients with acute lymphoblastic leukemia: are we there and are there pitfalls? | journal = Journal of Pediatric Hematology/Oncology | volume = 29 | issue = 12 | pages = 805–7 | date = December 2007 | pmid = 18090925 | doi = 10.1097/MPH.0b013e31815bbb83 }}</ref> and may have applications in treating other disorders such as ].<ref>{{cite journal | vauthors = Cuthbertson DJ, Babraj JA, Mustard KJ, Towler MC, Green KA, Wackerhage H, Leese GP, Baar K, Thomason-Hughes M, Sutherland C, Hardie DG, Rennie MJ | display-authors = 6 | title = 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men | journal = Diabetes | volume = 56 | issue = 8 | pages = 2078–84 | date = August 2007 | pmid = 17513706 | doi = 10.2337/db06-1716 | doi-access = free }}</ref> AICAR has been used clinically to treat and protect against cardiac ].<ref name="Corton_1995" /> The drug was first used in the 1980s as a method to preserve blood flow to the heart during surgery.<ref name="Galiñanes_1992">{{cite journal | vauthors = Galiñanes M, Bullough D, Mullane KM, Hearse DJ | title = Sustained protection by acadesine against ischemia- and reperfusion-induced injury. Studies in the transplanted rat heart | journal = Circulation | volume = 86 | issue = 2 | pages = 589–97 | date = August 1992 | pmid = 1638724 | doi = 10.1161/01.cir.86.2.589 | doi-access = free }}</ref>
			Acadesine is an adenosine regulating agent developed by PeriCor Therapeutics and licensed to Schering-Plough in 2007 for phase III studies. The drug is a potential first-in-class agent for prevention of reperfusion injury in CABG surgery. Schering began patient enrollment in phase III studies in May 2009. The trial was terminated in late 2010 based on an interim futility analysis.<ref>{{cite web | title = Research and Development Update | work = Merck & Co., Inc. | date = 30 June 2010 | url = https://www.sec.gov/Archives/edgar/data/310158/000095012310074336/y83714e10vq.htm#002 | quote = In the third quarter of 2010, the Company terminated the internal clinical development program for acadesine, an adenosine regulating agent for ischemia reperfusion injury in patients undergoing heart bypass surgery. Merck has decided to follow the recommendation of the independent Data Safety Monitoring Board (“DSMB”) to stop enrollment of the RED-CABG trial based upon the DSMB’s review of a pre-specified interim futility analysis which showed a low probability of the trial meeting its primary efficacy endpoint. }}</ref>
			==Chemistry==
			Reaction of 2-bromo tribenzoyl ] with ] results in the displacement of the anomeric halogen by one of the amino groups and the formation of the aminosugar largely as the β-]. Treatment of this product with ] in the presence of a base leads to the replacement of the alkoxy groups in orthoformate by the adjacent amines, resulting in the formation of the ] ring. Reaction with alkoxide then converts the nitrile nearest the sugar to an iminoester; the ] groups are cleaved in the process. ] in the presence of a ] and a base converts the iminoester to the corresponding primary amine. Basic hydrolysis then converts the remaining ] to an ], affording acadesine.<ref>{{cite journal | vauthors = Ferris JP, Devadas B, Huang CH, Ren WY |title=Nucleosides from carbohydrate adducts of diaminomaleonitrile. A novel synthesis of 5-amino-1-(.beta.-D-ribofuranosyl)imidazole-4-carboxamide and 5-amino-1-(.beta.-D-ribopyranosyl)imidazole-4-carboxamide|year=1985 |journal=The Journal of Organic Chemistry|volume=50|pages=747–754|issue=6 |doi=10.1021/jo00206a004}}</ref>
			]
			== Medical use ==
			A brief period of coronary arterial ] followed by ] prior to prolonged ischemia is known as ]. It has been shown that this is protective. Preconditioning preceded myocardial infarction, may delay cell death and allow for greater salvage of myocardium through reperfusion therapy.<ref name="Murry_1986">{{cite journal | vauthors = Murry CE, Jennings RB, Reimer KA | title = Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium | journal = Circulation | volume = 74 | issue = 5 | pages = 1124–36 | date = November 1986 | pmid = 3769170 | doi = 10.1161/01.cir.74.5.1124 | doi-access = free }}</ref> AICAR has been shown to precondition the heart shortly before or during ischemia.<ref name="Mullane_1993">{{cite journal | vauthors = Mullane K | title = Acadesine: the prototype adenosine regulating agent for reducing myocardial ischaemic injury | journal = Cardiovascular Research | volume = 27 | issue = 1 | pages = 43–7 | date = January 1993 | pmid = 8458030 | doi = 10.1093/cvr/27.1.43 | url = }}</ref> AICAR triggers a preconditioned anti-inflammatory state by increasing ] production from endothelial nitric oxide synthase.<ref>{{cite report | vauthors = Gaskin FS | title = Mechanisms of adenosine monophosphate-activated protein kinase-induced preconditioning in ischemia/reperfusion. | publisher = University of Missouri-Columbia | date = 2007 }}</ref> When AICAR is given 24 hours prior to reperfusion, it prevents post ischemic leukocyte-endothelial cell adhesive interactions with increased NO production.<ref name="pmid19152177">{{cite journal | vauthors = Gaskin FS, Kamada K, Yusof M, Durante W, Gross G, Korthuis RJ | title = AICAR preconditioning prevents postischemic leukocyte rolling and adhesion: role of K(ATP) channels and heme oxygenase | journal = Microcirculation | volume = 16 | issue = 2 | pages = 167–76 | date = February 2009 | pmid = 19152177 | pmc = 2784925 | doi = 10.1080/10739680802355897 }}</ref> AICAR-dependent preconditioning is also mediated by an ] and hemeoxygenase-dependent mechanism. It increases AMPK-dependent recruitment of ATP-sensitive K channels to the ] causing the ] duration to shorten, and preventing calcium overload during reperfusion.<ref name="Sukhodub_2007">{{cite journal | vauthors = Sukhodub A, Jovanović S, Du Q, Budas G, Clelland AK, Shen M, Sakamoto K, Tian R, Jovanović A | title = AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels | journal = Journal of Cellular Physiology | volume = 210 | issue = 1 | pages = 224–36 | date = January 2007 | pmid = 17044064 | pmc = 2128052 | doi = 10.1002/jcp.20862 }}</ref> The decrease in calcium overload prevents ] activation by ].<ref name="Tsuchida_1994">{{cite journal | vauthors = Tsuchida A, Yang XM, Burckhartt B, Mullane KM, Cohen MV, Downey JM | title = Acadesine extends the window of protection afforded by ischaemic preconditioning | journal = Cardiovascular Research | volume = 28 | issue = 3 | pages = 379–83 | date = March 1994 | pmid = 8174159 | doi = 10.1093/cvr/28.3.379 }}</ref> AICAR also increases AMPK-dependent glucose uptake through translocation of ] which is beneficial for the heart during post-ischemic reperfusion.<ref name="pmid10444490">{{cite journal | vauthors = Russell RR, Bergeron R, Shulman GI, Young LH | title = Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR | journal = The American Journal of Physiology | volume = 277 | issue = 2 | pages = H643–9 | date = August 1999 | pmid = 10444490 | doi = 10.1152/ajpheart.1999.277.2.H643 }}</ref> The increase in glucose during AICAR preconditioning lengthens the period for preconditioning up to 2 hours in rabbits and 40 minutes in humans undergoing coronary ].<ref name="Murry_1986" /><ref name="Burckhartt_1995">{{cite journal | vauthors = Burckhartt B, Yang XM, Tsuchida A, Mullane KM, Downey JM, Cohen MV | title = Acadesine extends the window of protection afforded by ischaemic preconditioning in conscious rabbits | journal = Cardiovascular Research | volume = 29 | issue = 5 | pages = 653–7 | date = May 1995 | pmid = 7606753 | doi = 10.1016/S0008-6363(96)88636-6| url = }}</ref> As a result, AICAR reduces the frequency and size of myocardial infarcts up to 25% in humans allowing improved blood flow to the heart.<ref name="Murry_1986" /><ref name="Mangano_1997">{{cite journal | vauthors = Mangano DT | title = Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group | journal = JAMA | volume = 277 | issue = 4 | pages = 325–32 | date = 1997 | pmid = 9002496 | doi = 10.1001/jama.277.4.325 }}</ref> As well, the treatment has been shown to decrease the risk of an early death and improve recovery after surgery from an ischemic injury.<ref name="Murry_1986" />
			==Pharmacology and use in doping==
			Acadesine acts as an ] agonist.<ref name="Corton_1995">{{cite journal | vauthors = Corton JM, Gillespie JG, Hawley SA, Hardie DG | title = 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? | journal = European Journal of Biochemistry | volume = 229 | issue = 2 | pages = 558–65 | date = April 1995 | pmid = 7744080 | doi = 10.1111/j.1432-1033.1995.0558k.x }}</ref> It stimulates ] and increases the activity of ] α and β in skeletal muscle tissue,<ref name="pmid12958172">{{cite journal | vauthors = Lemieux K, Konrad D, Klip A, Marette A | title = The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle | journal = FASEB Journal | volume = 17 | issue = 12 | pages = 1658–65 | date = September 2003 | pmid = 12958172 | doi = 10.1096/fj.02-1125com | doi-access = free | s2cid = 84040744 }}</ref> as well as suppressing ] by reducing production of reactive oxygen compounds inside the cell.<ref name="pmid18360094">{{cite journal | vauthors = Kim JE, Kim YW, Lee IK, Kim JY, Kang YJ, Park SY | title = AMP-activated protein kinase activation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) inhibits palmitate-induced endothelial cell apoptosis through reactive oxygen species suppression | journal = Journal of Pharmacological Sciences | volume = 106 | issue = 3 | pages = 394–403 | date = March 2008 | pmid = 18360094 | doi = 10.1254/jphs.FP0071857 | doi-access = free }}</ref>
			In 2008, researchers at the ] discovered that acadesine injected in mice significantly improved their performance in endurance-type exercise, apparently by converting fast-twitch muscle fibers to the more energy-efficient, fat-burning, slow-twitch type. They also looked at the administration of ] (also called GW1516) in combination with acadesine. Given to mice that did not exercise, this combination activated 40% of the genes that were turned on when mice were given GW1516 and made to exercise. This result drew attention to the compound as a possible athletic endurance aid.<ref name="pmid18674809">{{cite journal | vauthors = Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM | display-authors = 6 | title = AMPK and PPARdelta agonists are exercise mimetics | journal = Cell | volume = 134 | issue = 3 | pages = 405–15 | date = August 2008 | pmid = 18674809 | pmc = 2706130 | doi = 10.1016/j.cell.2008.06.051 }}</ref> One of the lead researchers from this study has developed a urine test to detect it and has made the test available to the ], and the ] (WADA) has added acadesine to the prohibited list from 2009 onwards.<ref> {{webarchive|url=https://web.archive.org/web/20090203030039/http://www.wada-ama.org/rtecontent/document/2009_Prohibited_List_ENG_Final_20_Sept_08.pdf |date=2009-02-03 }}</ref> The '']'' reported in 2009 that WADA had found evidence that acadesine was used by cyclists in the ].<ref>{{cite journal | vauthors = Benkimoun P | title = Police find range of drugs after trawling bins used by Tour de France cyclists | journal = BMJ | volume = 339 | pages = b4201 | date = October 2009 | pmid = 19825964 | doi = 10.1136/bmj.b4201 | s2cid = 45264608 }}</ref>
			== See also ==
			*]
			== References ==
			{{reflist|30em}}
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