O-304

O-304 is a synthetic small-molecule pan-AMPK (AMP-activated protein kinase) activator developed by Betagenon AB, a Swedish biotech that emerged from research at Umeå University. The compound directly binds and activates all AMPK isoforms, mimicking the kinase activation that normally occurs during energy stress, physical exercise, or caloric restriction. It is chemically a small molecule, not a peptide, but is studied alongside metabolic and exercise-mimetic peptides like MOTS-c, AICAR, and 5-Amino-1MQ.

AMPK is a heterotrimeric serine/threonine kinase that functions as the master energy sensor in eukaryotic cells. When cellular ATP drops and AMP rises, AMPK is activated and switches the cell from anabolic to catabolic metabolism: increased glucose uptake, increased fatty acid oxidation, decreased protein synthesis, decreased lipogenesis. Exercise activates AMPK in skeletal muscle. Metformin activates it indirectly through mitochondrial complex I inhibition. Direct pharmacological activation of AMPK has been a longstanding goal in metabolic drug development, complicated by the multiple AMPK isoform complexes with different tissue distributions.

O-304 is described as a "pan-AMPK activator" because it activates AMPK complexes containing different alpha, beta, and gamma subunit combinations rather than being selective for one isoform pair. The 2018 mechanism paper by Steneberg and colleagues in JCI Insight characterized the compound's activity across AMPK isoforms and reported broad metabolic effects in mouse models and the TELLUS Phase 2a trial in humans.

The Human Evidence

TELLUS Phase 2a trial. A 28-day proof-of-concept trial in 65 patients with type 2 diabetes already taking metformin. Results, published in the 2018 JCI Insight paper:

• Reduction in fasting plasma glucose
• Improvement in HOMA-IR (insulin resistance index)
• Lower systemic blood pressure
• Increased microvascular perfusion in calf muscle measured by contrast-enhanced ultrasound
• Well-tolerated over the 28-day exposure window

The trial was small and exploratory. It established proof-of-concept for direct AMPK activation in human metabolic disease but did not establish efficacy on hard cardiovascular or renal outcomes. Larger Phase 2b efficacy and Phase 3 trials have been pursued in diabetic kidney disease as a follow-on indication.

Phase 1 safety. Toxicology and Phase 1 safety studies in healthy volunteers established the dosing window subsequently used in TELLUS. No formal Phase 1 publication is available in PubMed.

The compound sits in early clinical territory rather than preclinical-only. The Phase 2a data is encouraging but does not constitute Phase 3 efficacy evidence.

Regulatory and Legal Status

FDA. Not approved. No marketing authorization submission as of May 2026.

EMA. Not approved.

Compounding. Not on the FDA bulk drug substances list. Compounding pharmacies do not produce O-304.

WADA. Not specifically named on the 2026 Prohibited List. The related AMPK activator AICAR is listed under Section S4 (Hormone and Metabolic Modulators). Athletes should treat AMPK activators as a monitored class.

O-304 is a direct allosteric activator of AMPK. The compound binds AMPK and stabilizes the active conformation of the kinase complex, increasing phosphorylation of downstream substrates. Unlike indirect activators (metformin, salicylates, AICAR) that work through changes in cellular AMP/ATP ratios or intermediates, O-304 directly engages AMPK protein structure.

Skeletal muscle effects. AMPK activation increases GLUT4 translocation to the plasma membrane and increases insulin-independent glucose uptake. The Steneberg et al. data showed this effect in mouse soleus muscle and in human Phase 2a microvascular perfusion measurements. The effect mirrors what happens during physical exercise.

Pancreatic beta cell effects. Animal data reported reduced beta cell stress markers and preserved beta cell function in diet-induced obese mice. The mechanism is hypothesized to reduce hyperglycemia-driven oxidative stress and preserve insulin-secretion capacity over time.

Cardiovascular effects. Mouse studies showed increased cardiac stroke volume and end-diastolic volume, reduced heart rate, and improved exercise capacity in both obese and aged mice. These effects mirror physiological adaptations to exercise training. The 2021 paper by Espinosa and colleagues extended the cardiovascular findings into aged-mouse models.

Renal effects. AMPK activation has been associated with reduced glomerular hyperfiltration and improved markers of diabetic nephropathy in animal models. Post-hoc analyses of Phase 1 and Phase 2a O-304 trial data have suggested reduced eGFR through a rapid, stable, and reversible hemodynamic mechanism. This has motivated the follow-on diabetic kidney disease development program.

Pharmacokinetics. Oral administration. Specific human half-life, Tmax, and steady-state data have not been published in detail in the open literature, but the once-daily dosing in the Phase 2a trial implies a multi-hour effective half-life.

Trial-documented effects from the TELLUS Phase 2a study in type 2 diabetes:

• Fasting plasma glucose reduction
• Insulin sensitivity improvement (HOMA-IR)
• Systolic blood pressure reduction
• Increased microvascular perfusion
• Reduced eGFR (kidney-relevant hemodynamic effect)
• Well-tolerated over 28 days

Animal data suggest additional effects not yet established in humans:

• Increased exercise endurance and stroke volume (mouse data)
• Reduced obesity-induced insulin resistance (mouse DIO models)
• Reversal of age-associated hyperinsulinemia (aged mouse data)
• Hepatic lipid metabolism shifts (rodent data)

Off-label adult research-chemical use is uncommon. The compound is not widely available outside investigational settings, distinguishing it from peptide compounds where research-chemical supply chains are well established.

The TELLUS Phase 2a trial used oral O-304 administered once daily over 28 days. Specific dose levels used in the trial have not been emphasized in the published summary; toxicology studies in rat and dog informed the human dose selection.

No FDA-approved dose exists because the compound is not approved. Phase 2a doses are the most reliable reference for what the trial program tested in monitored settings.

Off-label adult use outside investigational settings is uncommon. The compound is not produced by compounding pharmacies and is not widely available through research-chemical channels in the way that peptide compounds are. Sourcing risk is therefore both regulatory and identity-related.

The 28-day TELLUS Phase 2a trial described O-304 as well-tolerated. Specific adverse-event incidence rates have not been emphasized in the published summary, but no serious safety concerns terminated the development program. The follow-on diabetic kidney disease program has continued, suggesting the safety database has been adequate at the doses tested.

Class-effect safety considerations for AMPK activators include:

• Theoretical impact on adipose tissue metabolism with chronic activation
• Possible interactions with insulin-dependent and insulin-secretagogue diabetes medications
• Effects on bone and reproductive tissue (AMPK is expressed broadly)
• Cardiovascular effects requiring monitoring in patients with established disease
• Renal hemodynamic effects (the basis for the diabetic kidney disease indication exploration)

Long-term human safety data beyond the 28-day TELLUS exposure is limited. Phase 2b and Phase 3 trials in larger populations with longer dosing would provide the relevant data; these have not been published in full as of May 2026.

O-304 is the only direct small-molecule AMPK activator in late-stage clinical development. Within the metabolic and exercise-mimetic compound landscape, the closest research-chemical peers are AICAR (an AMP analog AMPK activator with WADA prohibition), 5-Amino-1MQ (NNMT inhibitor with separate metabolic effects), SLU-PP-332 (ERR agonist exercise mimetic), and the peptide MOTS-c (mitochondrial-derived peptide with broad metabolic effects).

The exercise-mimetic framing is shared across these compounds. None of them reproduces the full set of exercise benefits, which include musculoskeletal loading, cardiovascular conditioning, neural adaptations, and behavioral effects that no oral drug can replicate. The molecular-pathway claim is more defensible than the systemic-effect claim.

For type 2 diabetes specifically, the established comparator is metformin: a decades-long safety record, indirect AMPK activation, cardiovascular outcome data, and inexpensive generic availability. Direct AMPK activators like O-304 face the high bar of demonstrating advantage over metformin to justify replacement or add-on use in clinical practice. The TELLUS Phase 2a data established proof-of-concept but did not establish that advantage.

For informational and educational purposes only. Not medical advice. Not for human consumption unless prescribed by a licensed physician for an FDA-approved indication. Consult a qualified healthcare provider before using any peptide or pharmaceutical product.