Cardarine (GW-501516)

Cardarine is the common name for GW501516, also written GW-501516 or GW1516, a synthetic small molecule that selectively activates peroxisome proliferator-activated receptor delta (PPARδ). GlaxoSmithKline scientists reported it in 2001 (Oliver et al., 2001), and by 2006 GlaxoSmithKline and Ligand were developing it for dyslipidemia in phase II trials (Pelton, 2006).

Published work on GW501516 falls into six areas. Most of it is cell and animal research; the human data come from short studies in the development program and from anti-doping and toxicology work.

Discovery and selectivity

GlaxoSmithKline chemists found GW501516 by screening libraries of lipophilic carboxylic acids and refining the hits by structure-guided design into selective PPARδ agonists (Sznaidman et al., 2003). In macrophages, fibroblasts and intestinal cells it raised expression of the cholesterol transporter ABCA1 and induced apolipoprotein A1-specific cholesterol efflux (Oliver et al., 2001). Models: receptor assays and cultured cells.

Lipid and glucose metabolism in animals

In insulin-resistant, middle-aged obese rhesus monkeys, serum HDL cholesterol rose with increasing amounts of GW501516, while small dense LDL, fasting triglycerides and fasting insulin fell (Oliver et al., 2001). In rat L6 myotubes and mouse skeletal muscle it switched on genes for fatty acid transport, beta-oxidation and mitochondrial respiration; in mice fed a high-fat diet it reduced diet-induced obesity and insulin resistance, and in genetically obese ob/ob mice it lowered plasma glucose and insulin (Tanaka et al., 2003). Models: rhesus monkeys, rat muscle cells and mice.

Endurance studies in mice

In adult mice, a PPARδ agonist combined with exercise training increased oxidative muscle fibers and treadmill running endurance, while 4 weeks of the AMPK activator AICAR raised endurance by 44% even in sedentary mice, which the authors framed as overcoming the exercise requirement (Narkar et al., 2008). A doping-control review identifies the two compounds in that study as GW501516 and AICAR (Pokrywka et al., 2014). Model: mice.

Tumor findings and the end of development

In Apc(min) mice, which are prone to intestinal polyps, GW501516 increased the number and size of polyps, with a fivefold increase in polyps larger than 2 mm (Gupta et al., 2004).

Other work disagreed: in five human cancer cell lines, GW501516 and a second PPARδ agonist did not increase growth, Akt phosphorylation, VEGF or COX2 expression, and liver, colon and polyp tissue from mice given the agonists showed no change in those markers (Hollingshead et al., 2007). GlaxoSmithKline announced it would discontinue further research after preclinical studies in rodents linked the compound to widespread tumor development (Mackenzie and Lione, 2013). Models: mice and human cancer cell lines.

Human studies before development stopped

In the first report in people, healthy volunteers received GW501516 or placebo once daily for 2 weeks while hospitalized; HDL cholesterol rose relative to placebo and triglyceride clearance after a fat meal increased (Sprecher et al., 2007). A 2-week randomized, double-blind study in moderately overweight men reported lower fasting triglycerides, apolipoprotein B, LDL cholesterol and insulin, less liver fat and more fat oxidation (Risérus et al., 2008). Models: small, short human studies.

Anti-doping detection and toxicology

Anti-doping laboratories identified a sulfoxide and a sulfone as its two major urinary metabolites, using human liver microsomes and synthesized standards (Thevis et al., 2010). The parent compound has also been measured in human hair (Kintz et al., 2020). A 2021 case report describes liver cell injury and massive rhabdomyolysis in a man who had used GW501516 with a SARM (Kintz et al., 2021). Models: human liver microsomes, urine and hair samples, and a clinical case.