阿卡地新, Acadesine

5-Aminoimidazole-4-carboxamide-1-b-D-ribofuranose

Acadesine is a purine nucleoside analogue that inhibits the synthesis of ATP in cells. Acadesine blocks phosphorylation of adenosine monophosphate (AMP) to adenosine triphosphate (ATP) by inhibiting the activity of kinase-3, an enzyme involved in the production of ATP. Acadesine also inhibits the release of ATP from muscle cells into the blood stream and preferentially targets kidney cells, thereby reducing renal injury. Acadesine has been shown to be effective at reducing proteinuria and improving renal function in rats with acute kidney injury. Acadesine also has anti-inflammatory properties due to its ability to inhibit proteins that are involved in inflammation.

Cell-permeable activator of AMP-activated protein kinase. Is taken up into cells by adenosine transporters and phosphorylated by adenosine kinase to the active nucleotide ZMP (5-aminoimidazole-4-carboxamide ribonucleoside), which mimics effects of AMP on the AMPK system. Active in vivo and in vitro. Also available in simple stock solutions - add 1 ml of water to get an exact, ready-to-use concentration.

AICAR is an activator of AMP-activated protein kinase (AMPK). It increases AMPK kinase activity in isolated hepatocytes (EC50 = ~500 μM) and reduces HMG-CoA reductase activity and fatty acid and sterol synthesis in these cells. AICAR (0.5 mM) inhibits insulin-stimulated glucose uptake to 62% of control cells and reduces GLUT4 translocation by 2.5-fold in 3T3-L1 adipocytes. In astrocyte-enriched glial cells, AICAR (1 mM) prevents increases in protein levels of inducible nitric oxide synthase (iNOS), COX-2, and manganese superoxide dismutase (MnSOD) induced by LPS and amyloid-β (Aβ) (25-35) and expression of TNF-α, IL-1β, and IL-6 induced by LPS and Aβ42.3 AICAR inhibits autophagy in rat hepatocytes (IC50 = 0.3 mM) and induces apoptosis in rat β cells in a concentration-dependent manner.

Acadesine is a 5-aminoimidazole-4-carboxamide (AICA) riboside, a ribnucleoside analog, and a nucleotide biosynthesis precursor with B cell pro-apoptotic activity. Following cellular uptake, acadesine is phosphorylated to AICA ribotide (ZMP), which mimics 5'-adenosine monophosphate (AMP). Both AMP-activated protein kinase (AMPK) and AMPK kinase (AMPKK) are activated by ZMP, which appears to be necessary for the induction of apoptosis. Acadesine-induced apoptosis also appears to require cytochrome c release from mitochondria and caspase activation and is p53-independent. However, the exact mechanism of acadesine-induced apoptosis is unknown. T cells are significantly less susceptible than B cells to acadesine-induced apoptosis. AMPK regulates several cellular systems including the cellular uptake of glucose, the beta-oxidation of fatty acids, protein synthesis, and the biogenesis of glucose transporter 4 (GLUT4) and mitochondria.

Acadesine is a 1-ribosylimidazolecarboxamide in which the carboxamide group is situated at position 4 of the imidazole ring, which is further substituted at position 5 by an amino group. A purine nucleoside analogue and activator of AMP-activated protein kinase, it is is used for the treatment of acute lymphoblastic leukemia and is reported to have cardioprotective effects. It has a role as a platelet aggregation inhibitor and an antineoplastic agent. It is an aminoimidazole, a nucleoside analogue and a 1-ribosylimidazolecarboxamide.

Acadesine (AICA-riboside) is a purine nucleoside analog with anti-ischemic properties that is currently being studied (Phase 3) for the prevention of adverse cardiovascular outcomes in patients undergoing coronary artery bypass graft (CABG) surgery. It is being developed jointly by PeriCor and Schering-Plough. Acadesine has been granted Orphan Drug Designation for B-CLL in the EU.

Title: Acadesine

CAS Registry Number: 2627-69-2

CAS Name: 5-Amino-1-b-D-ribofuranosyl-1H-imidazole-4-carboxamide

Additional Names: 5-amino-4-imidazolecarboxamide ribonucleoside; AICA-riboside

Trademarks: Arasine (Gensia); Protara (Gensia)

Molecular Formula: C9H14N4O5

Molecular Weight: 258.23

Percent Composition: C 41.86%, H 5.46%, N 21.70%, O 30.98%

Literature References: Purine nucleoside analog. Prototype adenosine regulating agent; enhances endogenous adenosine levels in ischemic tissue. Biosynthesis, isoln, and characterization: G. R. Greenberg, E. L. Spilman, J. Biol. Chem. 219, 411 (1956). Chemical synthesis: J. Baddiley et al., Proc. Chem. Soc. London 1957, 149; J. P. Ferris et al., J. Org. Chem. 50, 747 (1985); T. Saito et al., Chem. Pharm. Bull. 42, 2263 (1994). Pharmacology: Z.-Q. Zhao et al., Cardiovasc. Res. 29, 495 (1995). Antiplatelet activity: D. A. Bullough et al., J. Clin. Invest. 94, 1524 (1994). Disposition and metabolism: R. Dixon et al., J. Clin. Pharmacol. 33, 955 (1993). HPLC determn in plasma: L.-S. Chen et al., J. Liq. Chromatogr. 18, 1451 (1995). Review of pharmacology: K. Mullane, M. Young, Drug Dev. Res. 28, 336-343 (1993); of development: K. Mullane et al., Trends Cardiovasc. Med. 3, 227-234 (1993). Meta-analysis of clinical trials in coronary artery bypass graft surgery: D. T. Mangano et al., J. Am. Med. Assoc. 277, 325-332 (1997).

Properties: Crystals from methanol or water, mp 213-214° (dec). Also reported as slightly brownish prisms from 90% aq ethanol, mp 206-208° (dec) (Saito). uv max (pH 7 and 1N NaOH): 265 nm (e 12400). uv max (1N HCl): 245, 265 nm (e 8670, 10320).

Melting point: mp 213-214° (dec); mp 206-208° (dec) (Saito)

Absorption maximum: uv max (pH 7 and 1N NaOH): 265 nm (e 12400); uv max (1N HCl): 245, 265 nm (e 8670, 10320)

Therap-Cat: Cardioprotective.

Keywords: Cardioprotective.