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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: Twitter: Dereklowe

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May 12, 2010

Insulin Degrading Enzyme's Turn in the Spotlight

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Posted by Derek

Well, you have to go back to the early days of this blog to find it, but I wrote here about insulin degrading enzyme. The name tells you some of what you need to know about it, for sure - it degrades insulin, so if you could stop that, insulin would probably hang around longer in the bloodstream. There's more to it - it's also been thought to be a way that insulin might be broken up inside cells as well, for one thing - but that's the elevator pitch for it.

And it has indeed been a diabetes target through the years. No one's come up with any really good inhibitors of it, although in vitro studies have been done with things like bacitracin and thioesters. Now a large multicenter academic team, led by the Mayo people from Florida, report some compounds that seem quite potent. (It's worth noting that these inhibitors are somewhat old news if you follow the patent literature).

The structures are not lovely, but there are a lot worse compounds in the protease inhibitor world. One thing that every experienced medicinal chemist will quickly notice about these is that they're hydroxamic acids. Those are compounds with a very spotty past in the business (although there is vorinostat (SAHA) out there on the market). Hydroxamates can be very potent inhibitors of metalloenzymes, and every time you target one they're always out there as a temptation, but the ugly clinical failures in that structural class tend to give people pause. Or was it just the targets (chiefly matrix metalloproteases) that the hydroxamates were aimed it? Have they been unfairly maligned? The arguments continue, and these compounds are unlikely to settle them.

Unless, of course, they go to the clinic and make a big success. I wonder if that's going to happen, though - the "go to the clinic" part, that is. This new paper is an interesting piece of work, and has a lot to say about the strange workings of IDE (which go a ways to explaining why there hasn't been much success targeting it - I was once involved briefly in the area myself). But it has nothing to say about whether these compounds have any exposure in any sort of animal, and that's the beginning of the really tricky part. These new compounds, in addition to be hydroxamic acids, are retro-inverso peptides. That's an old trick in the protease inhibitor world where you flip a natural sequence around and use the unnatural (D) amino acids to build it as well. Off the top of my head, I don't know of any retro-inverso compounds that have actually made it to market, although I'd be glad to be corrected on this.

The other complication will be IDE itself. One reason that no company has made a massive push on the target is that the enzyme is known to be multifunctional, as in "doing totally unrelated things all over the darn place", which makes one nervous about an inhibitor. Foremost among the off-target effects would be the beta-amyloid story (which is what led me to write about the enzyme back in 2003). IDE looks as if it could be one clearance mechanism for beta-amyloid (and perhaps for other easily-aggregating peptides), which has prompted people to think of actually trying to enhance its activity as an Alzheimer's therapy. One group that's tried this is, in fact, the same team that's now reporting the inhibitors (see this paper from 2009).

So I think these compounds will prove useful to figure out what IDE is doing, and that's a worthwhile goal. But I don't see them as drugs, no matter what the press release might say.

Comments (8) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History


1. DrJimbo on May 12, 2010 9:02 AM writes...

Well, an inhibitor that didn't cross the blood-brain barrier might get around some of the cured-your-diabetes-but-now-you've-got-Alzheimer's issues.

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2. RandDChemist on May 12, 2010 9:22 AM writes...

While there is substantial room for skepticism here, to be fair, they do seem to indicate that this is their lead to develop improved, more drug-like inhibitors.

"This crystal structure will facilitate the development of inhibitors that are more stable in the body than Ii1 is predicted to be."

The will certainly need to untangle the biology and think long and hard about using a hydroxamic acid. Interesting, but there is a long, hard road ahead for this one.

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3. partial agonist on May 12, 2010 11:36 AM writes...

It is important to note that even the press release does NOT call these compounds possible drugs, but rather it calls them compounds that "could lay the foundation for a new class of drugs for treating diabetes." I can't quibble at all with that language.

Also, big and non orally bioavailable "small molecules" can usually be discounted in the drug discovery business, but sales figures for Byetta make one pause a moment and say that maybe a good injectable could fly here. (Though Byetta is unusual in that much of its appeal is in its delayed gastric-emptying affect with accompanying appetite reduction, as opposed to glucose homeostasis.)

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4. anchor on May 12, 2010 11:37 AM writes...

Derek: MMP's (like IDE) are great target and the authors have unique opportunity to address issues related to diabetes. As I was going through this paper, medicinal chemist in me raised some red flags. The potent analog has a 2-naphthyl sub-unit and not long back we debated on this blog the merit(s) of drugs containing naphthyl group. This is a great compound for POC studies, but not as a drug. Your take as well as others on this subject are welcome.

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5. partial agonist on May 12, 2010 11:40 AM writes...

gastric-emptying effect, that is (not affect)...That's a pet peeve of mine when people mess that one up.

Corante could use an edit function!

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6. A Nonny Mouse on May 12, 2010 11:55 AM writes...

You forget that well known drug Ibuproxam, a pro-form of ibufrofen. There is also an animal heath product for arthritic dogs which is a hydroxamic acid.

To be truthful, none of these compounds is going to stick around for any length of time. The hydroxamic acid needs to be "reversed"in order to achieve sustained bio-activity with the N-formyl if Zinc attachment (antibiotics type) and N-acetyl of iron (5-LO inhibition). Good if you can also stick an alpha-methyl group there as well to stop NMAO activity...........I worked far too long of this class of compound

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7. Corpdoc on May 12, 2010 9:39 PM writes...

Bad target! Prolonged insulin exposure is not the answer. There are so many long acting, short acting, medium acting forms of insulin\ albeit controled by the rate of diffusion into the blood. But insulin has sytemic effects as a growth factor that are not ideal for diabetics. Not to mention that acute expostre to to much insulin can kill you faster than diabetes itself! Pulsitory deliver of insulin is the desired tratment preferably in direct response to blood glucose. These drugs woudl just be chsing the Insulin drug cash cow. At best a new long acting insulin...

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8. Scott on May 16, 2010 7:36 AM writes...

A Nonny Mouse...have you worked with SAHAs like vorinostat in the past? I was wondering what your thoughts were of its oncologic potential?

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