Acadesine
Encyclopedia
Acadesine (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, AICA-riboside
) 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.
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.
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 AICAR injected in experimental mice significantly improves 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 AICAR. 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 suggests it may be possible to obtain some of the benefits of exercising without actually exercising. Because of the enhanced endurance effects, this could potentially be used by athletes to enhance their performance. 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
has added AICAR to the prohibited list from 2009 onwards.
Riboside
A riboside is any glycoside of ribose. Ribosides in the form of ribonucleosides and ribonucleotides play an important role in biochemistry....
) is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
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.
Chemistry
Reaction of 2-bromo tribenzoyl riboseRibose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
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
Anomer
In carbohydrate chemistry, an anomer is a special type of epimer. It is one of two stereoisomers of a cyclic saccharide that differs only in its configuration at the hemiacetal or hemiketal carbon, also called the anomeric carbon. Anomerization is the process of conversion of one anomer to the other...
. 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
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
ring. Reaction with alkoxide then interestingly converts the nitrile nearest the sugar to an iminoester; the benzoyl
Benzoyl
In organic chemistry, benzoyl is the acyl of benzoic acid, with structure C6H5CO-. It should not be confused with benzyl, which is the radical or ion formed from the removal of one of the methyl hydrogens of toluene...
groups are cleaved in the process. Hofmann rearrangement
Hofmann rearrangement
The Hofmann rearrangement is the organic reaction of a primary amide to a primary amine with one fewer carbon atom.The reaction is named after its discoverer: August Wilhelm von Hofmann...
in the presence of a bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...
and a base converts the iminoester to the corresponding primary amine. Basic hydrolysis then converts the remaining nitrile
Nitrile
A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...
to an amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
, affording acadesine.
5-Aminoimidazole-4-carboxamide riboside
5-Aminoimidazole-4-carboxamide riboside acts as an AMP-activated protein kinaseAMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
agonist. It stimulates glucose uptake
Glucose uptake
Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion and secondary active transport .- Facilitated diffusion :There are over 10...
and increases the activity of p38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....
α and β in skeletal muscle tissue, as well as suppressing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
by reducing production of reactive oxygen compounds inside the cell.
In 2008, researchers at the Salk Institute discovered that AICAR injected in experimental mice significantly improves 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
GW 501516
GW-501516 is a PPARδ modulator compound being investigated for drug use by GlaxoSmithKline. It activates the same pathways activated through exercise, including PPARδ and AMP-activated protein kinase...
(also called GW1516) in combination with AICAR. 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 suggests it may be possible to obtain some of the benefits of exercising without actually exercising. Because of the enhanced endurance effects, this could potentially be used by athletes to enhance their performance. 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
International Olympic Committee
The International Olympic Committee is an international corporation based in Lausanne, Switzerland, created by Pierre de Coubertin on 23 June 1894 with Demetrios Vikelas as its first president...
, and the World Anti-Doping Agency
World Anti-Doping Agency
The World Anti-Doping Agency , , is an independent foundation created through a collective initiative led by the International Olympic Committee . It was set up on November 10, 1999 in Lausanne, Switzerland, as a result of what was called the "Declaration of Lausanne", to promote, coordinate and...
has added AICAR to the prohibited list from 2009 onwards.