AICAR Research, Specifications & Scientific Information

Introduction

AICAR is two compounds with one register record, and which one is meant depends entirely on who is speaking.

To a biochemist it is AICAR or AICA riboside: the standard cell-permeable reagent for switching on AMP-activated protein kinase, in use since a 1995 paper whose title posed the question that has followed it ever since — a specific method for activating AMP-activated protein kinase in intact cells? ^[1]. To a cardiac surgeon it is acadesine, an adenosine-regulating agent infused during bypass surgery, which went through five randomised trials in the 1990s and a phase 3 confirmatory trial in 2012.

The arc of that clinical programme is the most useful thing on this page. An individual-patient meta-analysis of the five trials, published in JAMA in 1997, reported a 27 per cent reduction in perioperative myocardial infarction and a 50 per cent reduction in early cardiac death ^[2]. Fifteen years later the confirmatory trial randomised 3,080 patients, was stopped for futility, and found the primary outcome in 5.0 per cent of the placebo group against 5.1 per cent of the treated group ^[4].

This page is a reference record. It describes research. It contains no guidance of any kind on handling the material.

What Is AICAR?

A purine nucleoside: 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide, molecular formula C9H14N4O5, molecular weight 258.23 g/mol. It is not a peptide, and it appears in this library under peptide-adjacent research compounds.

It is also an endogenous species. The compound is the riboside form of ZMP, an intermediate in de novo purine biosynthesis, which is the reason a cell has machinery for importing and phosphorylating it at all — and, as the mechanism section explains, the reason its selectivity has always been questioned.

The FDA/NCATS Global Substance Registration System carries it under UNII 53IEF47846 with CAS registry number 2627-69-2, PubChem compound identifier 17513, the International Nonproprietary Name acadesine, and a WHO anatomical therapeutic chemical code, C01EB13, in the cardiac therapy class. The presence of an ATC code alongside a ChEBI entry is a fair summary of the compound's double life.

It is not an approved medicine anywhere.

AICAR Specifications

AICAR is a purine nucleoside, not a peptide. It is recorded in the FDA/NCATS Global Substance Registration System under UNII 53IEF47846 with CAS registry number 2627-69-2, PubChem compound identifier 17513, molecular formula C9H14N4O5 and a molecular weight of 258.23 g/mol, under the International Nonproprietary Name acadesine and the WHO anatomical therapeutic chemical code C01EB13. It is also a naturally occurring intermediate: the riboside form of ZMP, which is an intermediate of de novo purine biosynthesis, and the reason the compound activates AMP-activated protein kinase at all is that the phosphorylated form it becomes inside the cell resembles adenosine monophosphate closely enough to occupy the same regulatory site. Two register names therefore describe one substance at two stages of its history — AICAR in the biochemical literature, acadesine in the clinical literature — and both refer to the compound described here. The register carries further identifiers including ChEBI, DrugBank, ChEMBL, an FDA orphan drug designation and a European orphan designation.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does AICAR Work?

Not directly. That is the whole of the mechanism and also the whole of the caveat.

AMP-activated protein kinase is the cell's sensor of adenylate status: when adenosine monophosphate rises relative to adenosine triphosphate, the kinase is activated, and it responds by switching catabolic pathways on and biosynthetic ones off. A compound that activated it would therefore be useful — but adenosine monophosphate itself cannot simply be added to cells.

AICAR is the workaround. It enters cells through nucleoside transporters and is phosphorylated by adenosine kinase to the monophosphate ZMP. ZMP resembles adenosine monophosphate closely enough to occupy the kinase's regulatory site and activate it ^[1]. The compound supplied is a precursor; the activator is what the cell makes from it.

Two consequences follow, and both are consequential.

Selectivity is not guaranteed. An adenosine monophosphate mimic accumulating inside a cell is available to every enzyme that responds to adenosine monophosphate, not only to AMP-activated protein kinase. The question mark in the 1995 title was deliberate, and it has never been removed.

The clinical framing was different. The cardiac surgery programme did not describe the compound as an AMPK activator. It described it as an adenosine-regulating agent, acting on adenosine handling during ischaemia and reperfusion ^[4]. Same molecule, same chemistry, a different account of which downstream consequence matters — and the trials tested the clinical framing.

AICAR Mechanism of Action

In vitro research

The founding methodological paper established both halves of the compound's reputation in one publication. It demonstrated that the ribonucleoside activates AMP-activated protein kinase in intact cells, which made a previously inaccessible pathway experimentally tractable, and it raised in its own title whether the method is specific ^[1].

That combination is why AICAR is simultaneously among the most-used reagents in metabolic cell biology and among the most caveated. A positive result obtained with it establishes that something in the cell changed when adenosine monophosphate mimicry was imposed. Attributing that change to AMP-activated protein kinase specifically requires a further control — a kinase-dead construct, a knockout, or a structurally unrelated activator — and papers that supply one are more informative than papers that do not.

Concentrations used in culture are typically well above physiological nucleoside concentrations, which compounds the selectivity question rather than resolving it.

What Is AICAR Being Researched For?

Three lines, with sharply different status.

• As a laboratory reagent. By far the largest use: activating AMP-activated protein kinase in cultured cells, across essentially every field that touches metabolism ^[1]. This is not research into the compound; it is research using it.
• Cardiac surgery. Closed. Five randomised trials pooled in 1997 ^[2], one phase 3 confirmatory trial stopped for futility in 2012 ^{[4, 7]}.
• Haematological malignancy. Early phase and small: a multicentre phase 1/2 study in relapsed or refractory chronic lymphocytic leukaemia ^{[6, 8]}, and a phase 1/2 trial in myelodysplastic syndromes terminated after five participants ^[9].

Preclinical metabolic work continues, and the best-known example is described in the preclinical section below.

None of the clinical work concerns research-grade material supplied for laboratory use.

Human Research on AICAR

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The meta-analysis of five trials

Population and design. Individual patient data from five randomised, placebo-controlled, double-blind trials across 81 medical centres in the United States, Canada and Europe: 4,043 patients undergoing coronary artery bypass graft surgery, 2,031 on placebo and 2,012 receiving the compound by intravenous infusion at 0.1 mg/kg per minute for seven continuous hours and via the cardioplegia solution. Inclusion criteria, methods and outcome assessment were similar across the five ^[2].

Result. Perioperative myocardial infarction fell by 27% (odds ratio 0.69; 95% CI 0.51–0.95; p = 0.02). Cardiac death through postoperative day 4 fell by 50% (OR 0.52; 95% CI 0.27–0.98; p = 0.04). The combined outcome of infarction, stroke or cardiac death fell by 26% (OR 0.73; 95% CI 0.57–0.93; p = 0.01). Cerebrovascular accident alone was not significantly reduced (OR 0.69; 95% CI 0.44–1.08; p = 0.10). A secondary analysis reported deaths following infarction through day 4 falling from 13 of 98 infarctions on placebo to 1 of 71 on the compound (p = 0.003). Use of ventricular assistance devices for severe postoperative heart failure fell by about one third (p = 0.05) ^[2].

Adverse events. Similar between groups, with the exception of a transient increase in serum uric acid in the treated group — which is what a purine nucleoside load would be expected to produce ^[2].

Limitations. A retrospective pooling of five separately designed trials, with the strongest single figure — the 89 per cent reduction in post-infarction death — resting on 14 events in total. Secondary analyses of small event counts are hypothesis-generating.

RED-CABG, the confirmatory phase 3 trial

Population and design. The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG trial: randomised, double-blind, placebo-controlled, parallel-group, in intermediate- to high-risk patients (median age 66) undergoing non-emergency on-pump bypass surgery at 300 sites in seven countries. Randomisation 1:1 to the compound at 0.1 mg/kg per minute for seven hours, also added to cardioplegic solutions, beginning just before anaesthesia induction. Enrolment ran from May 2009 to July 2010 ^{[4, 7]}.

Primary outcome. Composite of all-cause mortality, nonfatal stroke, or need for mechanical support for severe left ventricular dysfunction, through postoperative day 28 ^[4].

Result. A prespecified futility analysis indicated a very low likelihood of a statistically significant efficacious outcome, and the trial was stopped after 3,080 of a planned 7,500 participants were randomised. The primary outcome occurred in 75 of 1,493 (5.0%) on placebo and 76 of 1,493 (5.1%) on the compound (odds ratio 1.01; 95% CI 0.73–1.41). No differences were found in key secondary endpoints ^[4].

Why this result outranks the earlier one. RED-CABG was prospective, larger than any individual trial in the meta-analysis, designed specifically to test the hypothesis the meta-analysis generated, and it was stopped by a prespecified rule rather than a judgement call. An odds ratio of 1.01 is not a weak positive; it is the absence of an effect.

Haematological malignancy

A multicentre phase 1/2 study examined the compound in patients with relapsed or refractory chronic lymphocytic leukaemia ^{[6, 8]}. A separate phase 1/2 trial in myelodysplastic syndromes was terminated after enrolling five participants ^[9]. Neither programme has led to an approval.

Preclinical Research on AICAR

Animal research

The single best-known animal result in this literature is also the one most often quoted out of context.

A 2008 study in Cell examined orally active compounds acting on AMP-activated protein kinase and on the nuclear receptor PPARδ, and reported effects on endurance capacity and on metabolic gene expression in mice ^[3]. The framing the authors chose — compounds that mimic or potentiate the effects of endurance exercise — is what made the paper widely cited outside its field.

Two things about it deserve stating on a page like this. The work was in mice, at amounts and durations chosen for mice, measuring treadmill performance and transcriptional readouts. And the human programme for this same compound, which by 2008 had already run five randomised trials, was in an entirely unrelated indication and would fail its confirmatory trial four years later.

Metabolic remodelling agents including this compound have also been examined in the dystrophin-deficient mdx mouse ^[5].

Findings described in this section were observed in animals, and nothing in them establishes anything about humans.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

AICAR vs Related Compounds

The comparisons below are structural, mechanistic and evidential. No comparison of effect is made on this page.

SLU-PP-332 :: The other compound in this library described in the literature as acting on the same broad axis of metabolic transcription. It is a synthetic agonist at the oestrogen-related receptors, with no human data at all; AICAR is an endogenous nucleoside with a completed phase 3 trial. Same conversational category, opposite evidence positions.

Directness of action

AICAR does not bind its target. It is converted to ZMP inside the cell, and ZMP is the activator ^[1]. A compound that binds its receptor directly can be characterised by binding affinity; this one cannot, and its effective concentration depends on transport and phosphorylation as much as on the target.

NAD+ and 5-amino-1MQ :: Also grouped as peptide-adjacent research compounds and also concerned with metabolic cofactors and enzymes. Chemically unrelated to this compound and to each other.

Evidence base

AICAR has something almost nothing else in this library has — a large, prospective, adequately powered phase 3 trial that returned a clear null. That is more informative than a long list of positive small studies, and it is the reason the cardiac programme is closed.

Chemical & Molecular Characteristics

The register record is unusually rich. UNII 53IEF47846, CAS registry number 2627-69-2, PubChem compound identifier 17513, molecular formula C9H14N4O5, molecular weight 258.23 g/mol, International Nonproprietary Name acadesine, WHO ATC code C01EB13, plus ChEBI, ChEMBL, DrugBank, EPA CompTox and NSC identifiers, and both FDA and European orphan designations. That breadth reflects a compound that is simultaneously a natural metabolite, a research reagent and a former clinical candidate.

It is a nucleoside, and it behaves like one. Ribose joined to an aminoimidazole carboxamide base. Cells transport it as they transport other nucleosides and phosphorylate it as they phosphorylate other nucleosides, which is precisely why it works and precisely why it is not selective.

The uric acid signal is chemistry, not coincidence. The transient rise in serum uric acid reported in the pooled trials ^[2] is what would be expected from loading the purine pathway with an intermediate. It is a useful example of a pharmacodynamic observation that follows directly from a compound's structure.

The sequence fields are blank because there is no sequence. This is a small molecule of 258 daltons with no amino acids in it. It is listed as peptide-adjacent on the basis of the research questions it is used to answer, not on any structural relationship to the peptides in this library.

Frequently Asked Questions

Scientific References

1. Corton JM, Gillespie JG, Hawley SA, et al.. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? European journal of biochemistry; 1995. PMID 7744080 doi:10.1111/j.1432-1033.1995.tb20498.x
2. Mangano DT. 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 JAMA; 1997. PMID 9002496
3. Narkar VA, Downes M, Yu RT, et al.. AMPK and PPARdelta agonists are exercise mimetics Cell; 2008. PMID 18674809 doi:10.1016/j.cell.2008.06.051
4. Newman MF, Ferguson TB, White JA, et al.. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial JAMA; 2012. PMID 22782417 doi:10.1001/jama.2012.7633
5. Jahnke VE, Van Der Meulen JH, Johnston HK, et al.. Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model Skeletal muscle; 2012. PMID 22908954 doi:10.1186/2044-5040-2-16
6. Van Den Neste E, Cazin B, Janssens A, et al.. Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study Cancer chemotherapy and pharmacology; 2013. PMID 23228986 doi:10.1007/s00280-012-2033-5
7. The Effect Of Acadesine On Reducing Cardiovascular and Cerebrovascular Adverse Events In Coronary Artery Bypass Graft (CABG) Surgery (Study P05633 AM1)(TERMINATED) 2009. NCT00872001
8. Safety and Tolerability Open Label Dose Escalation Study of Acadesine in B-CLL Patients 2007. NCT00559624
9. GFM-Acadesine: A Phase I-II Trial of Acadesine 2013. NCT01813838

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.