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GW-501516(Cardarine) 1g

GW-501516(Cardarine) 1g

€45,00 EUR
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                                               NOT FOR HUMAN CONSUMPTION

Cardarine (GW501516), also known as Endurobol. is a high-affinity PPARβ/δ agonist developed in the 1990s for dyslipidemia, metabolic syndrome, and cardiovascular risk reduction. PPARδ activation remodels skeletal muscle, liver, adipose tissue, and macrophages toward fatty-acid oxidation (FAO), mitochondrial biogenesis (PGC-1α), and anti-inflammatory profiles. Development was halted after rodent carcinogenicity signals in long-term toxicology studies. GW501516 is not FDA/EMA approved, and all PPARδ agonists are prohibited by WADA.

Additional Benefits of GW501516 Now Under Investigation

Benefit Key take-aways
1 Endurance enhancement & metabolic reprogramming Strong upregulation of CPT-1, PDK4, UCP3, and oxidative myofiber gene sets; greatly improved time-to-exhaustion in rodents—an “exercise mimetic” phenotype. <br/>Cell Metabolism; Nature Medicine
2 Lipid optimization Marked TG ↓, VLDL ↓, HDL ↑, improved apoA-I dynamics, and reduced foam-cell formation—mechanistically attractive for atherosclerosis. <br/>ATVB; Circulation Research
3 Insulin sensitivity & glucose homeostasis Better HOMA-IR, increased muscle FAO, reduced hepatic steatosis, enhanced glucose uptake under insulin stimulation. <br/>Diabetes; JCI
4 Liver protection (NAFLD/MASH) Decreases hepatic fat, downregulates lipogenesis (SREBP-1c) and inflammation/fibrosis signals (TNF-α, TGF-β). <br/>Hepatology; Gastroenterology
5 Cardiovascular & endothelial benefits ↑ eNOS/NO, ↓ VCAM-1/ICAM-1, improves vascular relaxation, reduces atherosclerotic area in hyperlipidemic models. <br/>Circulation; Cardiovascular Research
6 Anti-inflammatory & immune modulation Represses NF-κB/AP-1 cytokine cascades; shifts macrophages away from inflammatory phenotype; improves colitis indicators. <br/>PNAS; Gut
7 Renal & pulmonary protection Reduces fibrosis and oxidative injury in ischemia-reperfusion kidney injury, and mitigates pulmonary hypertension/remodeling in PAH models. <br/>Kidney Int; AJP Lung
8 Neuroprotection & cognitive signals Improves mitochondrial efficiency and reduces microglial inflammation; modest benefits in toxin/aging models. <br/>Neurobiology of Aging; Glia
9 Metabolic flexibility under caloric load Enhances lipid oxidation during fasting/exercise and preserves glycaemic stability—attractive for metabolic-syndrome models. <br/>Cell Reports; Metabolism

2. Molecular Mechanism of Action

2.1 Receptor pharmacodynamics

  • PPARβ/δ agonist → heterodimerizes with RXR → binds PPRE → induces FAO, mitochondrial, and oxidative-gene expression.

  • FAO/mitochondrial genes: PGC-1α, CPT-1, ACOX1, UCP3, PDK4.

  • Anti-inflammatory effects: Transrepression of NF-κB/AP-1, reducing cytokines and adhesion molecules.

  • Macrophage lipid handling: ↑ ABCA1/ABCG1 → cholesterol efflux; ↓ foam-cell formation.

2.2 Down-stream biology

Pathway Functional outcome Context
PGC-1α–FAO program ↑ fatty-acid oxidation, ↑ endurance Skeletal muscle
ABCA1/ABCG1 Cholesterol efflux, anti-atherogenic Macrophages
NF-κB/AP-1 restraint ↓ cytokines/inflammation Vascular & immune
eNOS activation ↑ NO, endothelial function CV system
Anti-fibrotic (TGF-β) ↓ collagen deposition Liver/kidney/lung

3. Pharmacokinetics (preclinical & early clinical)

  • Route: Oral.

  • Half-life: Estimated 12–24 h in animals; human PK poorly published.

  • Absorption: Good oral bioavailability; highly lipophilic.

  • Distribution: Wide tissue distribution with liver and muscle enrichment.

  • Metabolism: Hepatic oxidative metabolism (CYP-mediated, details unpublished).

4. Evidence Summary

  • Metabolic disease: Strong rodent evidence for insulin sensitization, glucose-tolerance improvement, and NAFLD reduction.

  • CV disease: Reduced atherosclerosis and improved endothelial health.

  • Exercise physiology: Profound endurance gains in rodents via metabolic gene reprogramming.

  • Human trials: Only short Phase 1 safety studies; no efficacy trials completed.

Evidence quality note: Extensive animal and mechanistic literature but no validated human efficacy. Long-term rodent carcinogenicity at high exposures halted development.

5. Emerging Clinical Interests (conceptual)

Field Rationale Status
Metabolic syndrome/T2D FAO + insulin sensitivity ↑ Concept/preclinical
NAFLD/MASH Lipid handling + anti-inflammatory Preclinical
Atherosclerosis/CVD prevention Efflux + endothelial support Preclinical
PAH/fibrosis Anti-remodeling Preclinical
IBD/colitis Immune modulation Preclinical
Neurodegeneration Mitochondrial support Preclinical

6. Safety & Tolerability

6.1 Known/observed

  • Short-term (human Phase 1): Generally well tolerated, mild headache, nausea, or URI-like symptoms.

  • Metabolic effects: Beneficial lipids/glucose signals in animals; unknown long-term human impact.

6.2 Major concern: rodent carcinogenicity

  • Long-term GLP toxicology in multiple species showed rapid, high-incidence tumor formation across various tissues at pharma-scale exposures.

  • Mechanism unclear; may relate to PPARδ’s proliferative roles in some tissues.

6.3 Additional risks (theoretical/observed)

  • Carcinogenesis via β-catenin/TGF-β interactions (class concern).

  • Cardiac hypertrophy/arrhythmia signals absent in rodents but insufficiently studied in humans.

  • Hepatic drift at high doses.

  • Sport/anti-doping: Strictly prohibited by WADA (metabolic modulators).

Comparative matrix (class)

Feature GW501516 GW0742 Fenofibrate (PPARα)
Target PPARδ PPARδ PPARα
Human approval None None Yes (lipids)
Carcinogenicity Strong rodent signal Unknown No δ-class signal
Metabolic effects Strong Strong Moderate

7. Regulatory Landscape

  • Not approved by FDA/EMA/PMDA.

  • Development discontinued due to oncogenicity in animals.

  • Remains a research-only compound.

  • All PPARδ agonists = WADA prohibited.

8. Practical Take & Future Directions

  • No human self-use. Safety window unknown; serious carcinogenicity concerns.

  • Research directions:

    • Biased PPARδ agonists that retain FAO/mitochondrial benefits while reducing proliferative risk.

    • Tissue-targeted δ agonists (e.g., muscle-selective) to avoid systemic exposure.

    • Combination with GLP-1/GIP agonists or AMPK activators for metabolic synergy if safety improved.

  • Trial considerations (hypothetical): Require low-dose, short exposure, intense oncologic monitoring, and biomarker-driven go/no-go gating.

Selected References

  • Cell Metabolism; Nature Medicine — PPARδ-driven endurance and metabolic remodeling.

  • ATVB; Circulation Research; Cardiovascular Research — Lipid and atheroprotective effects; endothelial function.

  • Diabetes; JCI — Insulin-sensitizing and NAFLD improvements.

  • Hepatology; Gastroenterology — Anti-steatotic/anti-inflammatory liver results.

  • PNAS; Gut — Immune/NF-κB transrepression and colitis relief.

  • Kidney International; AJP Lung — Kidney/lung fibrosis and remodeling.

  • GLP toxicology datasets summarizing carcinogenicity outcomes (industry/EMA briefing notes).