# AICAR

> AICAR (acadesine) is a synthetic purine nucleoside analog, 5-aminoimidazole-4-carboxamide riboside, that is widely used in laboratory research as an activator of AMP-activated protein kinase (AMPK). It was first developed as a cardioprotective agent for coronary artery bypass surgery and was later studied in leukemia, metabolic and neuropathy models. It is not an FDA-approved drug.

Canonical: https://peptideproperties.com/compounds/aicar/

## Identity

- **Class:** Mitochondrial & Metabolic Research Compounds
- **Also known as:** Acadesine, AICA riboside
- **Molecular formula:** C9H14N4O5
- **Molecular weight:** 258.23 g/mol
- **Monoisotopic mass:** 258.0964 Da
- **CAS number:** 2627-69-2
- **PubChem CID:** 17513
- **InChIKey:** RTRQQBHATOEIAF-UUOKFMHZSA-N

## Key facts

- Class: purine nucleoside analog (imidazole riboside); laboratory AMPK activator
- Generic name acadesine; also called AICA riboside
- Formula C9H14N4O5; molecular weight 258.23 g/mol; CAS 2627-69-2
- Phosphorylated inside cells to ZMP (AICA ribotide), which activates AMPK
- Development codes include GP-1-110 and ARA-100
- Originally developed as an anti-ischemic agent for coronary artery bypass graft surgery
- Regulatory status: investigational; not FDA approved

## What Is AICAR?

AICAR is a small-molecule nucleoside, not a peptide, best known as a research tool for switching on AMPK, the cell's main energy-sensing kinase. Its full chemical name is 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, and its generic name is acadesine. A 2009 review described it as having been used extensively in vitro and in vivo to activate AMPK[1].Acadesine was initially developed as a cardioprotective agent. Its reported metabolic effects include release of adenosine as well as AMPK activation, and later work examined it as a candidate for B-cell chronic lymphocytic leukemia[2]. In the early 1990s it was described as a purine nucleoside analog with anti-ischemic properties in phase 3 study for patients undergoing coronary artery bypass graft (CABG) surgery[3].Terminology varies across papers. The compound itself is a riboside (a nucleoside without a phosphate). Once inside cells it is phosphorylated to AICA ribotide, abbreviated ZMP, and that monophosphate is the form linked to AMPK activation[4]. Some papers expand the acronym AICAR as the ribonucleotide, so readers should check which form a study actually used.

## Chemical Structure and Molecular Identity

AICAR consists of an imidazole ring carrying a 5-amino group and a 4-carboxamide group, joined at N1 to a β-D-ribofuranose sugar. PubChem lists the molecular formula C9H14N4O5 and a molecular weight of 258.23 g/mol under CID 17513, with CAS number 2627-69-2 and InChIKey RTRQQBHATOEIAF-UUOKFMHZSA-N.The molecule is small and highly polar. PubChem reports a calculated XLogP of −2.2, five hydrogen-bond donors and seven hydrogen-bond acceptors, reflecting the three ribose hydroxyls, the primary amine and the carboxamide. Structurally it resembles the natural purine nucleosides such as adenosine, which is why it is described as a purine nucleoside analog.
- Ring system: 5-aminoimidazole-4-carboxamide
- Sugar: β-D-ribofuranose with four defined stereocenters
- Intracellular metabolite: the 5′-monophosphate (ZMP)Chemists have used acadesine as a scaffold for analogs. One 2013 study synthesized derivatives in which the ribose ring was replaced by an acyclic D-ribityl chain or a 4-hydroxybutyl chain[5]. For quantitation, a spectrophotometric assay based on the Bratton-Marshall reaction for primary aromatic amines was developed to measure acadesine in human plasma, and it correlated closely with an HPLC method (r = 0.98)[6].

## Research History and Development

AICAR moved from a cardiac surgery drug candidate in the 1990s to a standard AMPK research tool and, later, a leukemia candidate. According to a 2008 drug profile, the original developer, Gensia Sicor, ran clinical trials in Canada, the EU and the US whose results were inconclusive[7].The same profile traces later licensing: rights for cardiovascular and cerebrovascular uses passed to Metabasis Therapeutics in 1997, then to PeriCor Therapeutics by sublicense in 2005, with Schering-Plough planning a randomized, placebo-controlled phase 3 trial in patients at high risk of ischemic heart events. Separately, acadesine was being co-developed for B-cell chronic lymphocytic leukemia (B-CLL)[7].Preclinical cardiac work supported the surgical program. A 1992 study tested acadesine in dogs on cardiopulmonary bypass subjected to global myocardial ischemia[8]. Human pharmacokinetic and metabolism data were published in 1993[3].The leukemia line of research began with a 2003 report that acadesine activated AMPK and induced apoptosis in B-CLL cells[4], followed by a 2010 review of its potential in hematologic malignancies[2]. In parallel, AICAR became a routine laboratory AMPK activator, although by 2009 reviewers were highlighting its AMPK-independent effects and calling for more selective activators[1].

## Mechanisms Studied in Research

AICAR acts mainly after cells take it up and convert it to ZMP, an AMP mimic that activates AMPK, but it also has effects that do not depend on AMPK. In B-CLL cells, blocking nucleoside transport with nitrobenzylthioinosine or blocking adenosine kinase with 5-iodotubercidin prevented both AMPK phosphorylation and apoptosis, showing that cellular uptake and phosphorylation to ZMP are required[4].
### AMPK-independent effects
A 2009 review noted that AICA riboside also acts on other AMP-regulated enzymes and on mitochondrial oxidative phosphorylation. In that work, the non-nucleoside activator A-769662 activated AMPK in rat hepatocytes without affecting oxidative phosphorylation or the cellular AMP:ATP ratio, in contrast with AICA riboside[1]. This is one reason findings obtained with AICAR alone are not always attributed to AMPK.
### Adenosine and other pathways
PathwayModelReported effectAdenosine releaseReview of preclinical and clinical dataDescribed as one of its broad metabolic effects[2]AMPK, ULK1 and mitophagyDorsal root ganglion neurons, diabetic miceHigher phospho-AMPK, DRP1, ULK1 Ser555 phosphorylation and LC3-II[9]SIK1Macrophages in vitroSuppressed inflammatory responses by modulating glucose and lipid metabolism[10]The 2008 drug profile classified acadesine as an adenosine receptor agonist[7], while the 1993 metabolism study called it an adenosine-regulating agent[3].

## Key Findings From Published Studies

Published findings combine cell and animal studies with early human pharmacokinetic and surgical trial data; no approved clinical use resulted.
### Cardiac ischemia (animal)
In dogs on cardiopulmonary bypass subjected to global warm ischemia followed by cardioplegic arrest, peak developed pressure recovered to 79% of baseline in the acadesine group compared with 56% in controls[8].
### Human pharmacokinetics
In four healthy men given radiolabeled acadesine by intravenous infusion, intact drug was measurable for only 2 hours. Uric acid was the main metabolite in plasma and urine, acadesine monophosphate was confined to red blood cells, and only 5% of the label was excreted in urine as unchanged acadesine[3]. A 2010 review stated that studies in healthy subjects and during CABG surgery showed acadesine to be devoid of serious toxicity[2].
### Leukemia cells (in vitro)
Acadesine induced caspase-dependent apoptosis in B-CLL cells from all 70 patient samples tested, without changing p53 levels. Normal B cells were equally sensitive, whereas T cells were only slightly affected and showed no AMPK phosphorylation[4].
### Neuropathy and joint models (animal)

- Diabetic polyneuropathy: AICAR prevented or reversed experimental neuropathy in mouse models of type 1 and type 2 diabetes. In high-fat-diet mice, the phospho-AMPK to total AMPK ratio in dorsal root ganglia rose 3-fold, and mitochondrial state 3 respiration, reduced to 120 nmol O2/min versus 220 in controls, measured 240 with AICAR[9].
- Osteoarthritis: AICAR, identified as an activator of SIK1, suppressed macrophage inflammatory responses in vitro, and a liposome-hydrogel formulation delivered into the joint mitigated osteoarthritis progression in vivo[10].Because AICAR, ZMP and related imidazole nucleosides are easy to confuse, researchers typically verify identity and purity with HPLC and mass-spectrometry certificates of analysis.Because AICAR, ZMP and related imidazole nucleosides are easy to confuse, researchers typically verify identity and purity with HPLC and mass-spectrometry certificates of analysis.

## Regulatory and Research Status

AICAR (acadesine) is not FDA approved for any use and remains an investigational compound and laboratory reagent. Its clinical development in cardiac surgery produced inconclusive trial results under the original developer, and a further phase 3 trial was planned as of 2008[7].In sport, AICAR is named as an example of an AMPK activator in the metabolic modulators section (S4) of the World Anti-Doping Agency Prohibited List. The current edition of that list is the authoritative reference.The evidence base consists of biochemical and cell studies, dog and mouse models, a small human metabolism study, and clinical trial programs summarized in drug-development reviews. Because AICAR has AMPK-independent actions, researchers increasingly pair it with more selective activators when attributing effects to AMPK[1].

## FAQ

**Is AICAR the same as acadesine?**
Yes. Acadesine is the generic name for AICAR, the nucleoside 5-aminoimidazole-4-carboxamide riboside, also called AICA riboside. Development codes such as GP-1-110 and ARA-100 refer to the same molecule. It should not be confused with ZMP, the phosphorylated ribotide that forms inside cells, although some papers use the AICAR acronym loosely for that form.

**Is AICAR a peptide?**
No. AICAR is a small-molecule purine nucleoside analog with the formula C9H14N4O5, made of an aminoimidazole carboxamide ring linked to a ribose sugar. It contains no amino acids. It is often discussed alongside metabolic research peptides such as MOTS-c because both are studied in connection with AMPK signaling.

**What is the molecular weight of AICAR?**
AICAR has a molecular weight of 258.23 g/mol according to PubChem (CID 17513). Its molecular formula is C9H14N4O5, its CAS number is 2627-69-2, and its InChIKey is RTRQQBHATOEIAF-UUOKFMHZSA-N. It is a highly polar molecule, with a calculated XLogP of -2.2.

**How does AICAR activate AMPK?**
AICAR enters cells through nucleoside transporters and is phosphorylated by adenosine kinase to ZMP, a monophosphate that mimics AMP and activates AMPK. In leukemia cell studies, blocking either uptake or phosphorylation prevented AMPK activation. Reviews note that AICAR also has AMPK-independent effects, including on mitochondrial oxidative phosphorylation.

**Is AICAR FDA approved?**
No. Acadesine has not been approved by the FDA for any indication. It was developed as an anti-ischemic agent for coronary artery bypass surgery and later studied for chronic lymphocytic leukemia, but early trials were reported as inconclusive. It is also listed by the World Anti-Doping Agency as a prohibited AMPK activator in sport.

**What does the research on AICAR show?**
Published studies report that AICAR activates AMPK and induces apoptosis in B-CLL cells in vitro, improved post-ischemic cardiac recovery in a dog bypass model, and prevented or reversed diabetic neuropathy in mouse models. A small human study described its rapid clearance and metabolism to uric acid. No approved clinical use has resulted.

## References

1. Guigas B, Sakamoto K, Taleux N, et al. Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB life 2009. PMID: 18798311
2. Van Den Neste E, Van den Berghe G, Bontemps F. AICA-riboside (acadesine), an activator of AMP-activated protein kinase with potential for application in hematologic malignancies. Expert opinion on investigational drugs 2010. PMID: 20367195
3. Dixon R, Fujitaki J, Sandoval T, et al. Acadesine (AICA-riboside): disposition and metabolism of an adenosine-regulating agent. Journal of clinical pharmacology 1993. PMID: 8227467
4. Campàs C, Lopez JM, Santidrián AF, et al. Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. Blood 2003. PMID: 12522004
5. D'Errico S, Oliviero G, Borbone N, et al. Synthesis of new acadesine (AICA-riboside) analogues having acyclic D-ribityl or 4-hydroxybutyl chains in place of the ribose. Molecules (Basel, Switzerland) 2013. PMID: 23924994
6. Fujitaki JM, Sandoval TM, Lembach LA, et al. Spectrophotometric determination of acadesine (AICA-riboside) in plasma using a diazotization coupling technique with N-(1-naphthyl)ethylenediamine. Journal of biochemical and biophysical methods 1994. PMID: 7836659
7.  Acadesine: AICA riboside, ARA 100, arasine, GP 1 110. Drugs in R&D 2008. PMID: 18457469
8. Bolling SF, Groh MA, Mattson AM, et al. Acadesine (AICA-riboside) improves postischemic cardiac recovery. The Annals of thoracic surgery 1992. PMID: 1610261
9. Chandrasekaran K, Choi J, Salimian M, et al. Administration of AICAR, an AMPK Activator, Prevents and Reverses Diabetic Polyneuropathy (DPN) by Regulating Mitophagy. International journal of molecular sciences 2024. PMID: 39795939
10. Fu Y, Hou J, Yang Q, et al. Liposome-encapsulated AICAR hydrogel regulates macrophage metabolic reprogramming via SIK1 activation to alleviate osteoarthritis. Journal of nanobiotechnology 2025. PMID: 40616103