AICAR

AICAR (acadesine) is best known as an 'exercise mimetic,' studied for reproducing some effects of endurance training, like better stamina and fat burning, without exercise. It works by activating AMPK, a cellular energy sensor; it's a small molecule (a nucleoside analogue), not a peptide. It is not FDA-approved for any use: a Phase 3 heart-surgery trial was stopped for futility and development was discontinued, and today it's sold only as a research compound.

AICAR has been studied as an "exercise mimetic" — a compound meant to reproduce some effects of endurance training. The foundational finding is preclinical: a mouse study reported that four weeks of AICAR alone increased running endurance by 44% without training. No published human trial has reproduced an exercise-mimetic effect at realistic doses, and reported effects in human trials of the drug include raised uric acid (hyperuricemia).

Not FDA-approved for any indication. Acadesine (AICAR) was advanced through Phase III clinical evaluation by Pericor Therapeutics / Schering-Plough / Merck for cardioprotection during coronary artery bypass graft (CABG) surgery in the late 2000s and 2010 — the RED-CABG Phase III trial was terminated for futility in 2010 after interim analysis showed no benefit on the primary composite endpoint.[⁴] Clinical development was discontinued. Available exclusively as a research compound through unregulated research-supply chains. Not DEA-scheduled. WADA-banned in regulated sport — listed under Section S4.4.1 (activators of the AMP-activated protein kinase (AMPK) and PPARδ agonists, within the Metabolic Modulators class S4.4) of the 2026 Prohibited List as "AICAR" and "GW1516" — a different WADA subsection from the GHRP-class compounds (S2.2.4) and the AAS class (S1).[³] Recent doping context: AICAR has been at the center of multiple high-profile doping investigations in cycling and endurance sports since ~2009 — predating WADA's formal addition of metabolic modulators to the Prohibited List in 2009 and continuing as a high-priority Athlete Biological Passport target.

AICAR is not FDA-approved, and its exercise-mimetic effect in humans is not established by clinical trials. It is banned in regulated sport (named on the WADA Prohibited List under metabolic modulators — Section S4.4.1, AMPK activators). VialWise is a research and educational reference, not medical advice — consult a licensed professional.

⚠️ For research and educational purposes only. AICAR (acadesine) is not approved by the FDA for any indication. Acadesine Phase III clinical development for cardioprotection during CABG surgery (the RED-CABG trial) was terminated for futility in 2010. AICAR is available exclusively as a research compound through unregulated supply chains. Information in this entry is informational, not medical advice. Always confirm dose calculations with the in-app calculator and consult appropriate professional guidance before any protocol decisions.

⚠️ AICAR is a nucleoside analog, not a peptide. Unlike the majority of the Vialwise library, AICAR is a small-molecule nucleoside (MW 258.23 Da) that is phosphorylated intracellularly to AICA-ribotide ("ZMP"), an AMP-mimic that activates AMP-activated protein kinase (AMPK). This places AICAR mechanistically and pharmacologically distinct from peptide-axis compounds in the library — the cluster context is exercise-mimetic compounds (SLU-PP-332, MOTS-c, AICAR), not the GHS-axis or HPG-axis peptide clusters.

⚠️ The Narkar 2008 *Cell* "exercise mimetic" finding is foundational but is preclinical (mouse) data — the human exercise-mimetic effect has not been demonstrated in published clinical trials. The Narkar 2008 study found that 4 weeks of AICAR alone (/day IP) in sedentary adult mice produced a 44% increase in treadmill running endurance without any exercise training, accompanied by induction of metabolic genes including oxidative-fiber and fatty-acid-oxidation markers.[¹] This is the foundational exercise-mimetic finding that anchored research-community use of AICAR. However: (a) the dose was very high ( in mice translates to ~ in humans by body-surface-area scaling, or ~2.8 grams in a 70-kg adult — far higher than any clinically-studied human acadesine dose); (b) IP administration in mice does not translate cleanly to SC or oral administration in humans; (c) no published human RCT has reproduced the exercise-mimetic effect at translationally-relevant doses. Research-community use of AICAR for exercise-mimetic effects in humans operates on a substantial gap between preclinical and clinical evidence.

⚠️ AICAR has multiple safety considerations distinct from the peptide-cluster compounds in the library. Three load-bearing pharmacological concerns: - Cardiac AMPK activation alters myocyte contractility. The Oliveira 2012 *Circulation Research* study established that AICAR-induced AMPK activation in murine cardiomyocytes phosphorylates cardiac troponin I at Ser150, increasing myofilament Ca²⁺ sensitivity, increasing myocyte contractility, and prolonging relaxation — even without changing the amplitude or decay-time-constant of Ca²⁺ transient.[²] The clinical implication is that AICAR alters cardiac contractile function at the molecular level; whether this is beneficial (cardioprotective during ischemia) or concerning (in healthy young athletes) depends on context. The acadesine cardioprotective hypothesis was the basis for the Phase III red-cabg trial; the trial's failure (terminated for futility)[⁴] means the cardioprotective effect did not translate to a clinically-meaningful CABG outcome. - Hyperuricemia. AICAR-derived ZMP enters purine metabolism and produces dose-dependent hyperuricemia in published human clinical trials — typically asymptomatic and transient but a recognized lab-monitoring concern. - Possible glucose dysregulation. AMPK activation increases glucose uptake into skeletal muscle (GLUT4 translocation) and decreases hepatic gluconeogenesis. In healthy humans these effects are likely subclinical; in individuals with diabetes, glucose-lowering medications, or impaired glucose tolerance, the AMPK-activation pathway may produce unexpected hypoglycemia.

⚠️ WADA-banned under Section S4.4.1 (activators of the AMP-activated protein kinase (AMPK) and PPARδ agonists, within the Metabolic Modulators class S4.4) — a different WADA subsection from the GHS-axis (S2.2.4) and AAS (S1) classes that dominate the rest of the library. The 2026 WADA Prohibited List Section S4.4.1 names "AICAR" and "GW1516" explicitly among the prohibited metabolic modulators — the verbatim S4.4.1 text reads: *"Activators of the AMP-activated protein kinase (AMPK), e.g. AICAR and MOTS-c; and Peroxisome Proliferator Activated Receptor δ (PPARδ) agonists, e.g. GW1516 (GW501516)."*[³] AICAR is a non-Specified Substance, prohibited at all times in and out of competition, and the exercise-mimetic cluster sibling MOTS-c shares this exact subsection (S4.4.1). AICAR has been a high-priority Athlete Biological Passport target since ~2009 following multiple high-profile cycling-sport doping cases — the WADA testing apparatus monitors AICAR/ZMP analytes as part of routine sample analysis. AICAR is one of the substances explicitly identified in the post-Operación Puerto era as having been used by elite endurance athletes.

According to PubMed-indexed research, AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) is a nucleoside analog that activates AMP-activated protein kinase (AMPK) via intracellular phosphorylation to AICA-ribotide ("ZMP").[¹] AMPK is the master cellular energy sensor — heterotrimeric kinase complex (α/β/γ subunits) that is allosterically activated when AMP rises relative to ATP at the γ-subunit nucleotide-binding domain. ZMP mimics AMP at this site, producing AMPK activation in the absence of true energy depletion. The pharmacological effect mimics the metabolic state of exercise or caloric restriction — including increased glucose uptake into skeletal muscle (via GLUT4 translocation), increased fatty-acid oxidation, decreased hepatic gluconeogenesis, and induction of mitochondrial-biogenesis and oxidative-fiber gene-expression programs.

The "exercise mimetic" finding (Narkar 2008 Cell). The foundational research-community-relevant publication is the Narkar 2008 *Cell* paper, *"AMPK and PPARdelta agonists are exercise mimetics."*[¹] Sedentary adult male C57BL/6 mice received AICAR alone (/day intraperitoneal) for 4 weeks without any exercise training. AICAR treatment alone induced metabolic genes and enhanced running endurance by 44% vs. vehicle-treated sedentary controls — establishing the "exercise mimetic" framing that has anchored research-community use of AICAR since. The same Narkar paper found that the PPARβ/δ agonist GW1516 synergized with exercise training to further increase oxidative-fiber composition and endurance. AICAR and GW1516 are the foundational "exercise mimetic" small molecules — both are now WADA-prohibited and both are heavily monitored in endurance-sport doping surveillance.

Acadesine cardioprotection clinical development history. AICA-riboside is a naturally-occurring intermediate of the *de novo* purine-synthesis pathway; exogenous administration was first characterized as an AMPK activator in the late 1980s and subsequently developed as the investigational drug acadesine (Gensia Pharmaceuticals, later Pericor Therapeutics). AICAR was originally advanced into clinical development under the INN "acadesine" for cardioprotection during CABG surgery — the hypothesis being that AMPK activation during ischemia-reperfusion injury would limit infarct size and reduce post-CABG cardiovascular complications. Early Phase II/III trials in the 1990s (multinational acadesine cardioprotection program) showed mixed signals. The 2010 RED-CABG Phase III trial (NCT00872001; Pericor Therapeutics, partnered with Schering-Plough → Merck) enrolled cardiac-surgery patients at elevated risk of post-operative cardiovascular events. The trial was stopped for futility on a prespecified interim analysis after 3,080 of a projected 7,500 participants were randomized, with the primary composite endpoint (cardiovascular death, MI, stroke) occurring in 5.0% of placebo vs 5.1% of acadesine patients (OR 1.01, 95% CI 0.73–1.41) — no benefit.[⁴] Clinical development for cardioprotection was discontinued after RED-CABG. Beyond cardioprotection, acadesine was also evaluated in early-phase oncology — Phase 1/2 studies in B-cell chronic lymphocytic leukemia (NCT00559624, completed) and higher-risk myelodysplastic syndromes/CMML (NCT01813838, terminated) — but no subsequent Phase III trial of acadesine, in any indication, has been registered.

Cardiac AMPK activation pharmacology (Oliveira 2012).[²] The Oliveira 2012 *Circulation Research* study used a yeast 2-hybrid screen against the N-terminal 273 residues of the AMPK γ2 subunit to identify cardiac troponin I as an AMPK substrate. In vitro studies established that AMPK phosphorylates cardiac troponin I at Ser150, with increased Ca²⁺ sensitivity of contractile regulation per actomyosin ATPase and demembraneated trabecular force measurements. Treatment of murine cardiomyocytes with AICAR resulted in increased myocyte contractility without changing the amplitude of Ca²⁺ transient, and prolonged relaxation despite shortening the time constant of Ca²⁺ transient decay (tau). The AMPK inhibitor Compound C prevented the AICAR effect, establishing AMPK-dependence. The Oliveira study established that AICAR alters cardiac function at the molecular level via AMPK-mediated phosphorylation of cTnI — a finding relevant to both the cardioprotective hypothesis (positive: improved ischemic tolerance) and the safety concern (positive inotropy + prolonged relaxation may not be desirable in all populations).

Exercise-mimetic cluster context. AICAR sits in the small-but-growing "exercise mimetic" mechanism cluster of the Vialwise library alongside: - SLU-PP-332 — small-molecule ERR (estrogen-related receptor) agonist exercise mimetic; preclinical data show endurance and metabolic-gene induction effects parallel to AICAR; clinical translation pending. The closest mechanism-cluster sibling to AICAR. - MOTS-c — mitochondrial-derived peptide; AMPK-pathway-activating effects overlap with AICAR; entirely-different chemical class (12-amino-acid peptide vs nucleoside analog) but converging mechanism. - AOD-9604 — synthetic lipolytic fragment of GH; different mechanism (lipolysis-direct) but adjacent body-composition-research use case.

The exercise-mimetic cluster is the most-rapidly-evolving area in the broader "metabolic modulator" research space and is the focus of substantial WADA testing-development attention.

Doping-context history. AICAR has been at the center of multiple high-profile doping investigations in cycling and endurance sports since ~2009. Key context: - WADA formally added "metabolic modulators" to the Prohibited List in 2009 following intelligence suggesting AICAR was being used by elite endurance athletes (cycling primarily, but also middle/long-distance running). AICAR was named explicitly in the 2009 list. - Several high-profile non-analytical anti-doping cases in cycling (2009–2014) involved AICAR among other substances. AICAR's relatively short plasma half-life was the basis for assumed washout-before-testing strategies — strategies that became less effective as WADA's analytical methods improved. - Athlete Biological Passport (ABP) era — modern WADA testing relies on longitudinal biomarker profiles rather than detection of intact AICAR; AICAR-induced changes in hematological and metabolic biomarkers can be detected via ABP even after the drug itself is cleared.

Regulatory status (US — current). AICAR is not FDA-approved for any indication. Acadesine clinical development was discontinued after RED-CABG failed in 2010. The compound is available exclusively as a research compound through unregulated research-supply chains; not legally compoundable through US 503A pharmacies. Not DEA-scheduled.

Regulatory status (sport — WADA). AICAR is WADA-banned under Section S4.4.1 (activators of the AMP-activated protein kinase (AMPK) and PPARδ agonists, within the Metabolic Modulators class S4.4) of the 2026 Prohibited List, named explicitly as "AICAR" alongside GW1516 and other metabolic modulators.[³] Prohibited at all times. AICAR has been a high-priority Athlete Biological Passport target since ~2009.

Common research interests. Despite the absent published-clinical-evidence base for the exercise-mimetic effect, AICAR is used in research-community contexts for: - Putative exercise-mimetic / endurance-enhancement effects — the dominant research-community use case, anchored on the Narkar 2008 *Cell* finding[¹] despite the substantial preclinical-to-clinical translation gap. - Putative fat-loss / body-composition effects — secondary research-community use case, anchored on AMPK activation's role in fatty-acid oxidation and energy-expenditure modulation. - Adjunct to other AMPK-pathway compounds — combined with metformin, resveratrol, or other AMPK-pathway modulators in research-community body-composition protocols.

Commonly reported

• Hyperuricemia — dose-dependent; the most-commonly-reported lab abnormality in acadesine clinical trials and research-community use. Typically asymptomatic but a recognized monitoring concern.
• Elevated plasma lactate — transient; reported in acadesine clinical trials
• Injection-site reactions — typical of subcutaneous administration
• Headache — uncommon; reported in some acadesine clinical trials
• Nausea — uncommon; reported in some acadesine clinical trials, particularly with oral administration
• Cardiac contractility / relaxation alterations — characterized at the molecular level in preclinical work[²]; whether this produces subjective cardiac symptoms in research-community use is unclear
• Long-term safety in humans using AICAR off-label is essentially uncharacterized. The acadesine clinical-trial dataset is short-duration (CABG perioperative use); chronic human use is not characterized in published literature.
• The exercise-mimetic effect in humans is not established by published clinical trials. The Narkar 2008 finding[¹] is mouse data; no human RCT has reproduced the effect at translationally-relevant doses.
• AMPK-mediated effects on lipid metabolism are complex — net effect on body composition in humans is not well-characterized.

Serious

• Acute gout attack — possible in individuals with predisposition; sudden severe joint pain (typically first metatarsophalangeal joint) with redness/swelling warrants medical evaluation
• Severe hyperuricemia with renal symptoms (decreased urine output, flank pain) — could suggest urate nephropathy; rare but warrants immediate medical evaluation
• New-onset arrhythmia or chest pain — given the Oliveira 2012 cardiac AMPK-cTnI finding,[²] new-onset cardiac symptoms warrant immediate medical evaluation and discontinuation
• Severe hypoglycemia — particularly when combined with diabetes medications; warrants immediate carbohydrate administration and medical evaluation
• Allergic reaction (hives, swelling, difficulty breathing) — extremely rare but warrants immediate medical evaluation

Active gout or hyperuricemia — AICAR exacerbates uric acid elevation

Active cardiac arrhythmia or heart failure — theoretical concern given Oliveira 2012 cardiac AMPK-cTnI findings[²]

Pregnancy and lactation — no human data; default to contraindicated

Pediatric use — no clinical-trial evidence base; default to contraindicated

Concurrent insulin or sulfonylurea antidiabetic therapy — hypoglycemia risk

Concurrent xanthine-oxidase inhibitors (allopurinol, febuxostat) — purine-metabolism interaction

Active malignancy — AMPK pathway effects on tumor growth are complex and bidirectional; default to caution

Regulatory note (US): AICAR is not FDA-approved for any indication and is not legally compoundable through US 503A pharmacies.

Regulatory note (sport): WADA-banned under Section S4.4.1 (AMPK activators, within the Metabolic Modulators class S4.4) of the 2026 Prohibited List.[³] Prohibited at all times. Athlete Biological Passport surveillance is active.

Not DEA-scheduled.

Small molecule

A low-molecular-weight chemical compound, distinct from peptides and proteins.

AMPK

A cellular "master energy sensor" enzyme; when activated, it shifts metabolism toward burning fat and taking up glucose, mimicking some effects of exercise or fasting.

Preclinical

Research done in cells or animals, before human clinical trials. Promising preclinical results don't always hold up in people.

WADA Prohibited List

The list of substances banned in regulated sport by the World Anti-Doping Agency.

Exercise mimetic

A compound that activates some of the same cellular pathways as exercise; the term is mechanistic and does not mean it replaces training.

1. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. (2008). AMPK and PPARdelta agonists are exercise mimetics. Cell, 134(3):405–415 (July 31, 2008).(PMID 18674809)
2. Oliveira SM, Zhang YH, Solis RS, Isackson H, Bellahcene M, Yavari A, Pinter K, Davies JK, Ge Y, Ashrafian H, Walker JW, Carling D, Watkins H, Casadei B, Redwood C. (2012). AMP-activated protein kinase phosphorylates cardiac troponin I and alters contractility of murine ventricular myocytes. Circulation Research, 110(9):1192–1201 (March 27, 2012).(PMID 22456184)
3. World Anti-Doping Agency. The 2026 Prohibited List, International Standard (effective 1 January 2026). Canonical PDF: wada-ama.org/sites/default/files/2025-09/2026list_en_final_clean_september_2025.pdf (linked from the WADA landing page; local archival copy in `docs/legal/wada-2026-prohibited-list.pdf`). AICAR is named under Section S4.4.1 — the AMP-activated protein kinase (AMPK) activators and PPARδ agonists subsection of the Metabolic Modulators class (S4.4) — a different subsection from the GHRP-class compounds (S2.2.4) that anchor most of the Vialwise library's WADA cross-references. Verbatim S4.4.1 text: "Activators of the AMP-activated protein kinase (AMPK), e.g. AICAR and MOTS-c; and Peroxisome Proliferator Activated Receptor δ (PPARδ) agonists, e.g. GW1516 (GW501516)." AICAR is a non-Specified Substance, prohibited at all times; the exercise-mimetic cluster sibling MOTS-c shares this exact subsection.
4. Newman MF, Ferguson TB, White JA, Ambrosio G, Koglin J, Nussmeier NA, Pearl RG, Pitt B, Wechsler AS, Weisel RD, Reece TL, Lira A, Harrington RA. (2012). Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA, 308(2):157–164.(PMID 22782417 · NCT00872001)

• SLU-PP-332 — discussed together in this entry's stacks section
• MOTS-c — discussed together in this entry's stacks section
• ACE-031 — same mechanism class
• 5-amino-1MQ — same mechanism class
• Follistatin — shared research area
• HGH (Human Growth Hormone) / Somatropin — shared research area