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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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January 19, 2012

Dapagliflozin Goes Down (For the Last Time?)

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Posted by Derek

To no one's surprise, the FDA has rejected dapagliflozin, an SGLT2 inhibitor for diabetes. The advisory panel voted it down back during the summer, and the agency has asked AstraZeneca and Bristol-Myers Squibb to provide more safety data. As it stands, the increased risk of bladder and breast cancer (small but significant) that was seen in the clinic just outweighs the drug's benefits.

That's the sodium-glucose cotransporter 2, and what it does normally is reabsorb glucose in the kidney to keep it from going on into the urine and being lost. It's been the subject of quite a bit of drug development over the last few years, with the thought being that spilling glucose out of the bloodstream, as an adjunct to other diabetes therapy, might be more of a feature than a bug.

Not with that safety profile, though. And since this compound has been through nearly a dozen different advanced trials in the clinic, I really don't see how anyone's going to be able to provide any safety data at this point to change anyone's mind about it. Type II diabetes is an area with a lot of treatment options, and while all of them have their advantages and disadvantages, taken together, there's quite a bit than can be done. So if you're going to enter a crowded field like this, a new mechanism is a good idea (thus SGLT2). But you're also up against a lot of things that have proven themselves in the real world, some of them for a long time now, so your safety profile has to be above reproach.

Canagliflozin, from J&J, is still out there in the clinic, and you can bet that the folks there will be digging through the data from every direction. Are dapagliflozin's problems mechanism-related, or not? Would you care to spend nine figures to find out? That's how we do it around here. . .

Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity | Toxicology


COMMENTS

1. milkshake on January 19, 2012 3:34 PM writes...

agents that produce bladder cancer are quite often electrophilic metabolites from oxidative activation. To me, on the first glance, that ethoxybenzyl looks like place where one would expect the cytochromes to take a bite at the molecule, possibly generating species that can result in a stabilized benzylic cation or a quinoid. The J&J drug does not have this feature although the thiophene is another piece liable to be oxidized apart...

Permalink to Comment

2. B on January 19, 2012 5:37 PM writes...

The interesting thing is that Steve Nissen, who slammed Avandia over it's safety has discounted the concerns over dapagliflozin.

"The prominent cardiovascular expert Steve Nissen has discounted any link with cancer and highlighted the therapeutic effects of the drug."

Permalink to Comment

3. PharmaHeretic on January 19, 2012 5:55 PM writes...

100 hospitalized after German university experiment goes wrong (Jan 19, 2012, 20:00 GMT)

http://www.monstersandcritics.com/news/europe/news/article_1686416.php/100-hospitalized-after-German-university-experiment-goes-wrong

Dresden, Germany - Around 100 people were hospitalized late Thursday after a chemistry experiment at a German university went wrong, emergency services and a university spokeswoman said.

... It was not immediately clear how the accident had occurred but it possibly involved arsine, a compound of arsenic and highly toxic. ...

Permalink to Comment

4. tuky tuky on January 19, 2012 6:39 PM writes...

#1 - 2,5-substituted thiophenes are "safer" than the unsubstituted ones in terms of glutation metabolism

Permalink to Comment

5. anonymous on January 19, 2012 8:40 PM writes...

Derek:
Relative to your comment "Type II diabetes is an area with a lot of treatment options", you might also want to include the addendum "many of which, especially the oral agents, do not exhibit robust efficacy as monotherapy"....

Permalink to Comment

6. PharmaHeretic on January 19, 2012 9:15 PM writes...

Any thoughts on how large amounts of arsine were involved in an explosion? and why were 100 or more people affected? Isn't that a large number for a lab mishap?
---

Hundreds Reportedly Injured in Chemical Explosion at German University

http://gizmodo.com/technical-university-of-dresden/

Permalink to Comment

7. Rock on January 19, 2012 10:33 PM writes...

There is more than the J&J compound still out there. At last count there were at least five or six SGLT2 inhibitors in the clinic. Sorry to see dapagliflozin go down, it was a great med chem story.

Permalink to Comment

8. Anonymous on January 20, 2012 3:17 AM writes...

to the Dresden accident: only 3 of them showed slight symptoms, the rest of the "hundred injured" were just hospitalized as a precaution. Also no explosion took place, just some gas but they're not sure, probably because its gone already.

Permalink to Comment

9. anchor on January 20, 2012 7:17 AM writes...

@ Milkshake; great point! CYP mediated oxidative de-ethylation can be a big deal as also the straight oxidation of the benzyl appendage. I wonder if the medicinal chemist "plugged" all these soft spots to arrive at better analog.

Permalink to Comment

10. Anonymous on January 20, 2012 4:17 PM writes...

Major metabolite of dapa in humans is the glucoronide. Metabolism differs across the species, but the observation of the glucoronide as the major human excreted metabolite has been reported. The cancer uptick is most likely an example of detection bias among bladder and breast cancer patients, but without the evidence to prove that, the FDA rejected it. Unfortunately, as this first-in-class may go, it should help the followers be aware of safety issues to address. I don't think we've heard the last of the SGLT2 class.

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