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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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April 12, 2013

PPAR Delta For Cycling? I Think Not.

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Posted by Derek

Now here's one that I didn't know about: a reader sends along word that the former clinical candidate GW501516 is enjoying some popularity on the black market among cyclists and other athletes.

I remember that compound well from the days when I did PPAR nuclear receptor research. It's the very model of a PPAR-delta ligand - GlaxoSmithKline had it in the clinic for some time, until it slowly disappeared from their roster. In 2007, the Evans lab at the Salk Institute published a paper suggesting that the compound increased endurance, and that sent it right into the athletic underworld. I have no idea if it does what its users want, but I do know that I wouldn't touch the stuff. The PPAR compounds have a very, very wide range of effects, and unraveling those proved to be very difficult indeed. Long-term effects of a compound like this one are unknown - all we know is that GSK dropped it from the clinic, and that could well have been for tox. Taking this stuff to gain some time in a bicycle race is sheer foolhardiness.

Comments (26) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Ben Zene on April 12, 2013 9:33 AM writes...

Nah, these days everyone is after AICAR.

http://www.guardian.co.uk/sport/2009/oct/06/tour-de-france-undetectable-drugs

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2. ton on April 12, 2013 9:34 AM writes...

yeah, that's scary on several levels. 1) they'd be willing to take compounds that were pulled from trials for safety. 2) there are commercial sources that mention the "potential benefits" but don't mention the safety issues aside from saying "not for human consumption"

but, just to add to the toxic fun, people are taking 2,4-DNP for weight loss...

http://www.livestrong.com/article/527267-dnp-and-weight-loss/

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3. Rhenium on April 12, 2013 10:21 AM writes...

Bicycle raise?

Race maybe?

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4. milkshake on April 12, 2013 10:29 AM writes...

wikipedia article mentions that the compound is a potent carcinogen in rodents...

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5. followerchemist on April 12, 2013 10:45 AM writes...

Most performance enhancing drugs, even if the substance is usually benign, are pretty horrible on your health as the dosage is generally very high. Not to mention that a successful bike racing career (5 or more grand tours, dozens of classics and loads of other shorter events) is reckoned by some to shorten your life expectancy too, these guys prob just think it's an occupational hazard. Also there recruited because of there legs not that ability to make sensible life choices!

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6. Millard Baker on April 12, 2013 10:58 AM writes...

@followerchemist I agree that elite cycling is not so much about health. I'd even say that cycling itself is potentially more damaging to health than performance-enhancing drugs.

But you are wrong about the dosages of most PEDs being high in cycling - for example, the performance-enhancing dosages of EPO and testosterone are generally within therapeutic dosage range.

While few people overestimate the prevalence of doping in sports, most tend to overestimate the dosages used. Some sports the dosages are high, but most are not.

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7. JoJo on April 12, 2013 10:58 AM writes...

I thought you were such a big supporter of phenotypic screens.

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8. NR dude on April 12, 2013 11:07 AM writes...

#4: PPAR ligands of all types tend to be rodent carcinogens

#6:

Adding T to eugonadal men in the therapeutic range does almost nothing, except make your balls shrink and your prostate get bigger. Not exactly the combo most people look for. Anabolic effects generally at levels higher than reproductive ones and T provides no discrimination.

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9. johnnyboy on April 12, 2013 11:22 AM writes...

I heard of elite triathletes who liked to down a very tall glass of DMSO after training...
Elite sport is by definition foolhardiness. Elite athletes care about one thing, and one thing only. It is by definition a completely unbalanced lifestyle, which is why an inordinate number of them end up prematurely dead, disabled, mentally unstable, or in jail.

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10. ed on April 12, 2013 11:48 AM writes...

an inordinate number of them end up prematurely dead, disabled, mentally unstable, or in jail.

...or confessing to Oprah.

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11. Anonymous on April 12, 2013 12:36 PM writes...

@Milkshake - I see a lot of the bodybuilding forums are suggesting taking a COX2 and GW516. Combination therapy in a phenotypic screen no less

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12. Sam Weller on April 12, 2013 12:40 PM writes...

#8: At least in cycling, smaller balls are an advantage ;)

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13. paperclip on April 12, 2013 1:58 PM writes...

I wonder, though, how many times the racer wins just from the placebo effect.

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14. Boghog on April 12, 2013 2:00 PM writes...

@NR dude:

But this one appears to be an especially potent carcinogen:

2 year rodent carcinogenicity tests:
all species (mouse + rat), both sexes, multiple organs, and showed carcinogenic effects at the lowest dose tested

The FDA generally classifies such substance as probable human carcinogens.

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15. followerchemist on April 12, 2013 2:07 PM writes...

@millard baker I did say generally... the performance enhancing affects of EPO do start within the therapeutic range (particularly on the big tours where levels of lots of essentials are low) although EPO dosages were high enough to be thought to be responsible for several (as many as 15, or more) heart attacks in physically fit 25-35 year olds in the 90s, I believe this was due to blood thickening, although my EPO knowledge comes from cycling not science... Although there were some different attitudes doping in the 80s as talked about by Dr Bellocq taking small amounts of hormones etc during races keeping them within "natural levels". All very interesting science-wise though if you know more about it would be very interested :)

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16. Lyle Langley on April 12, 2013 2:30 PM writes...

@Sam Weller, #12.

I think it is also fewer in number that help.

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17. Imaging guy on April 12, 2013 3:44 PM writes...

I agree with # 13 paperclip. Since no clinical trials are done, I doubt the effectiveness of these performance-enhancing drugs. When you do clinical trials, most of the drugs for medical treatment are found to be ineffective or produce minimal benefits as well as side-effects.

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18. Rev. Howard Furst on April 12, 2013 4:02 PM writes...

Reminds me that Dr. Evans brushed me off rather impolitely when I raised the carcinogenicity issue after his talk at a Keystone meeting in 2006... Another victory for the GSK diligence team or more likely some jaboney overriding their judgment.

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19. another process chemist on April 12, 2013 6:46 PM writes...

#13, #17 – I doubt that the placebo effect plays a major role in the context of doping in cycling, in part because the impact of PED use is only partially exerted in competition. When you look at the type of programs that were prevalent in the 1990s and 2000s, one could argue that the primary role of PEDs was to enable riders to ride more training miles than would have been possible if they were clean. The over-training threshold was effectively raised, and this is a primarily a physiological threshold, not a psychological one.

That said, the truth here will vary by the substance. Riders will take stimulants due to their ability to reduce perceived exertion, so the placebo effect should be high here.

With something like testosterone, there could be some placebo effect, but the feeling of dead legs after riding 100+ miles in the Alps is very tangible, so an alleviation of this would need to have at least some physiological basis.

Something like EPO in and of itself should have minimal placebo effect, since with the more sophisticated teams, its uses has been not so much as a means of boosting total blood cell count but rather to balance out the population of blood cells. Autologous blood doping leaves a person with an inordinate amount of older erythrocytes, and this imbalance is easily detectable. EPO can fill in the population of younger erythrocytes to rebalance. You could argue that the act of augmenting your hematocrit could have a placebo effect in addition to the enhanced oxygen transport it offers, but I’d suggest that the extra oxygen plays a bigger role than the extra confidence (especially after a long day in the saddle).

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20. Nick on April 13, 2013 12:24 AM writes...

There are a few studies showing the effects of EPO on performance, and even more showing the effects of blood transfusions.

Even at the low levels of EPO usage in trials it showed substantial improvement. Unsurprisingly ethical issues have stopped studies where EPO levels simulated those used in professional cycling.

If it's placebo, it's a bloody effective one. Eg, the EPO era in cycling is generally accepted to be 1993 to 2006. Look at the top 100 times up Alpe du Huez: http://www.fillarifoorumi.fi/forum/showthread.php?38129-Ammattilaispy%F6r%E4ilij%F6iden-nousutietoja-%28aika-km-h-VAM-W-W-kg-etc-%29&p=2004795#post2004795

(only 1 of them is post 2006)

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21. Anonymous BMS Researcher on April 13, 2013 7:03 AM writes...

The SF novel Achilles Choice by Niven and Barnes describes a future when athletes cannot compete at the highest levels unless they undergo deadly enhancements.

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22. Thomas on April 13, 2013 5:16 PM writes...

I wonder where the athletes buy this substance... it does not look like a trivial molecule to me.

Can something like this be synthesized on demand for a reasonable cost and purity/safety?

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23. anonymous on April 14, 2013 10:21 AM writes...

Can anyone share the REAL story why the Clinical developement of this molecule was terminated?
PS - @18 Not unusual for Dr. Evans to rudely dismiss ANYONE who disagrees w/ him !!

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24. NHR_Guy on April 14, 2013 4:25 PM writes...

Ahhh Yes....PPAR delta. I made a living off that target. I ran a PPAR delta program in big pharma. We had some very selective compounds (much more than GW's 50516). We could never seem to get over the SKM tox though. I was never convinced it was tox per se, but cells transforming from white to brown adipose. I remember a comment from one of the vets handling our studies in beagles. He said the dosed cohort looked like they had been bodybuilding, very muscular and lean, with very little visceral fat. I always thought we had a drug, but just couldn't meet the pre-clin safety bar

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25. Boghog on April 15, 2013 4:44 AM writes...

@23:

There were reports before 2006 showing that GW501516 had tumor promotion effects (see for example PMID:15867396). GSK has stated on their web site that development of the compound was halted in 2006 (search for GW501516 on the GSK dot com website). I do not have any inside information, but based on the published reports of tumor promotion effects, it certainly would be prudent to complete the two year rodent tox tests (that are required for regulatory approval) before expensive phase 3 studies were initiated. It appears that the tox test were completed after 2006. Whether the development of the drug was put on hold or terminated in 2006 is a matter of semantics. It is clear however that after the results of the tox tests, the drug would have no chance of approval.

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26. exGlaxoid on April 15, 2013 8:40 AM writes...

I don't know the exact reason that 516 was first pulled for, but it did have some issues in tox. We made a series of related compounds for several years, and many were more potent or more selective, but none ever made it much further; I think by that time the PPAR train had derailed. But I am certain that there were much better ones at GSK than 516 in most ways. Don't know if much was ever published, as most of those chemists were downsized in 2008, and that makes it hard to publish the data.

It is interesting to think that it sells for $100/g now, I made grams of many derivatives for animal studies, most were likely tossed afterwards. I guess I should learn to save samples for future "studies".

I think that the FDA might be made less relevant in this age where nearly anyone can buy anything from China and people can research science on the web in seconds. This may allow in-vivo research, much like when scientists used to study drugs on prisoners, only with less scientific oversight. Much like the Shulgin self experimentation. Now if only we could get all of those scientists to self-publish as well.

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