Mighty Mouse drugs

This article in Cell Metabolism is getting a lot of attention, and for good reason: PPARδ Promotes Running Endurance by Preserving Glucose. I highly recommend the original article, as its chock-full of great references regarding all things PPARδ. For the layman, here’s the Nature News writeup (Athletic endurance enhanced by metabolic shift) and Discover writeup (With An Injection, Mice Nearly Double Their Endurance), which are great for distilling the original research paper down to the important bits. But this headline from Endpoints is eye catching: A new Mighty Mouse drug, making marathon runners with a pill. That last headline…! Who wouldn’t want to take a pill that would turn them into Mighty Mouse? Of course, this particular Mighty Mouse drug is on WADA and MLB’s lists of banned substances. And it’s not what you might think it is.

When most people think of performance enhancing drugs, they first think of steroid analogues and stimulants. But PPARδ agonists are a separate class of performance enhancing drugs, having an entirely different mechanism of action. Peroxisome proliferator-activated receptors (PPAR) have been popular targets in pharmaceutical research for decades. Activation of PPARs is thought to improve the body’s response to insulin, and a few diabetes drugs have arisen from this line of thought. You may be familiar with Actos and Avandia, and you may also be familiar with a string of lawsuits related to the safety of these drugs. Actos and Avandia activate the alpha and gamma PPAR subtypes, which are widely expressed throughout the body. Activation of the delta subtype hasn’t been explored as closely since the delta subtype wasn’t identified until much later. Because PPAR delta (PPARδ) is still expressed in adipose tissue, but not in heart tissue, researchers hope that activation of PPARδ will still provide a therapeutic effect in diabetic and overweight patients, without the nasty cardiovascular side effects. But as noted in the Cell Metabolism article, activation of PPARδ has implications in increasing athletic endurance in subjects who aren’t overweight or diabetic – hence the Mighty Mouse label from Endpointswhich brings us back to MLB’s lists of banned substances.

The MLB list recites “Metabolic Modulators, including Peroxisome Proliferator Activated Receptor δ (PPARδ) agonists, including GW 1516, GW 0742, and AICAR”. AICAR is an adenosine monophosphate (AMP) derivative. The other two of the three specific compounds listed, GW 1516, and GW 0742, are of a similar structural class – GW 1516, also known as GW501516, is the compound in the Cell Metabolism article. GW 1516 is also known as Endurobol; it was initially a drug candidate but was abandoned due to adverse side effects. The side effects are so severe (cancer!) that WADA even added extra warnings to athletes regarding its use. But when someone calls it a “Mighty Mouse drug”, you have to wonder if someone is going to look to another PPARδ agonist as a way to gain an advantage. There are other PPARδ agonists reported in the literature, although the language of the MLB banned substance list doesn’t limit the banned PPARδ agonists to the three compounds that are explicitly recited. But I wonder – how are WADA and MLB testing for other PPARδ agonists if there is no core structural feature? Are they actually testing for metabolites of other PPARδ agonists? Or are they simply hoping that no one will try a newer PPARδ agonist, for fear of potential side effects?

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