Acadesine

Not to be confused with 5-aminoimidazole-4-carboxamide ribotide.

Acadesine

File:Acadesine structure.svg
Systematic (IUPAC) name
5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-imidazole-4-carboxamide
Identifiers
CAS Number	2627-69-2 N
ATC code	C01EB13 (WHO)
PubChem	CID: 17513
IUPHAR/BPS	5133
ChemSpider	16560 Y
UNII	53IEF47846 Y
KEGG	D02742 Y
ChEBI	CHEBI:28498 N
ChEMBL	CHEMBL1551724 N
Chemical data
Formula	C9H14N4O5
Molecular mass	258.231 g/mol
SMILES O=C(c1ncn(c1N)[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)CO)N
InChI InChI=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 Y Key:RTRQQBHATOEIAF-UUOKFMHZSA-N Y
NY (what is this?)  (verify)

Acadesine (INN), also known as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, AICA-riboside, and AICAR, is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia and may have applications in treating other disorders such as diabetes.

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.

Chemistry

Reaction of 2-bromo tribenzoyl ribose with 1,2-diaminomaleionitrile results in the displacement of the anomeric halogen by one of the amino groups and the formation of the aminosugar largely as the β-anomer. Treatment of this product with methyl orthoformate 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 imidazole ring. Reaction with alkoxide then interestingly converts the nitrile nearest the sugar to an iminoester; the benzoyl groups are cleaved in the process. Hofmann rearrangement in the presence of a bromine and a base converts the iminoester to the corresponding primary amine. Basic hydrolysis then converts the remaining nitrile to an amide, affording acadesine.

File:Acadesine.png

Acadesine

Pharmacology and use in doping

Acadesine acts as an AMP-activated protein kinase agonist. It stimulates glucose uptake and increases the activity of p38 mitogen-activated protein kinases α and β in skeletal muscle tissue, as well as suppressing apoptosis by reducing production of reactive oxygen compounds inside the cell.

In 2008, researchers at the Salk Institute 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 GW 501516 (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. One of the lead researchers from this study has developed a urine test to detect it and has made the test available to the International Olympic Committee, and the World Anti-Doping Agency (WADA) has added acadesine to the prohibited list from 2009 onwards. The British Medical Journal reported in 2009 that WADA had found evidence that acadesine was used by cyclists in the 2009 Tour de France.