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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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February 3, 2010

Dimebon for Alzheimer's: A Black Box Indeed

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Posted by Derek

Dimebon (dimebolin) is a perfect example of the black-box nature of drug research for the central nervous system. Any medicinal chemist who looks at its structure would immediately say "CNS", but shrug when asked what specific receptors it might hit. I'd have guessed histamine (correctly), since loratidine used to pay my salary, and I also would have guessed a clutch of 5-HT stuff as well. But it also has activity at AMPA and NMDA glutamate receptors, L-type calcium channels, and more. If you can tell me what it's really doing up there, you shouldn't bother: hang up on me and start calling people with money, because you're ready to take over the CNS therapeutic area for sure.

This blunderbuss is getting a lot of attention these days, since the data for a Phase III trial against Alzheimer's should be available sometime in the spring. The road to that was a strange one. Dimebolin was used for years as an antihistamine in Russia, although I'm not aware if it had any particular reputation for cognitive enhancement in its time as a Soviet allergy pill. It was picked up in screening done during the 1990s at a research institute in the (once secret) military/industrial research city of Chemogolovka Chernogolovka, about two hours from Moscow. It showed effects on learning in rodent models, and gradually advanced to human trials for Alzheimer's. Impressive data came out in 2008, and Medivation, who own the rights to it here, partnered with Pfizer for development.

Update: the city mentioned above is surely Chernogolovka, but it's interesting that it's appeared many times as Chemogolovka in the English press and literature. I chalk that up to the "rn" looking very much like an "m", and to the mistaken name being semi-plausible in a Stalinist-industrial way, as witness Magnitogorsk. Chernogolovka's much older, though.)

That Bloomberg report I linked to above has a lot of people excited, since there hasn't been a new therapy for Alzheimer's in quite a while (or, arguably, a decent one ever). I don't know what to think, myself. It's absolutely possible that the drug could turn out to have beneficial effects, but it's just as possible that it could miss meeting the high expectations that many investors seem to have for it. (Medivation's stock is up 80% over the last year, for example). A lot of eye-catching numbers from small Phase II trials tend to flatten out in the wider world of Phase III, and if forced, that's the way I'd bet here. (I am most definitely not giving investment advice, though - Alzheimer's drug development is a total crap shoot, and should only be approached with money you can afford to see incinerated).

I hope that Dimebon actually works, though - the world could use something that does. Just don't let anyone convince you that they know how it works, if it makes it through. Unraveling that will take quite a while. . .

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | The Central Nervous System


1. PharmaHeretic on February 3, 2010 8:52 AM writes...

I would hasten to add that good results in phase II trials have often turned to dust in Phase III, especially for AD. It is as if there was a vested interest in "getting" exciting Phase II results and then giving the bagholders a useless compound.

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2. retread on February 3, 2010 9:29 AM writes...

The fact that dimebon is active at many different receptors isn't bad. I watched people get out of wheelchairs when L-DOPA was released for Parkinsonism 9/70 in the US (Europeans had been using it for years -- thank you FDA which wouldn't accept these studies). We were supplying the 'missing' transmitter.

One can produce memory deficits reminiscent of Alzheimer's disease using muscarcinic cholinergic blockers (scopolamine, atropine), so the great hope with the anticholinesterase drugs was that we were bucking up acetyl choline neurotransmission (which presumably was all that was wrong in Alzheimer's).

Despite all the hype (primarily by the drug companies and academia), I never saw a really useful clinical effect on cognition with any of them (nor did any clinical neurologist I knew) until I retired in '00. Hopefully things are better now, but I doubt it, if my uncle and parents of friends are any example. The 'benefit's' shown in studies on large numbers are no doubt real, but too small to be clinically useful.

Probably one reason for this, is that multiple neurotransmitters are known to be involved in Alzheimer's, of which acetyl choline is but one. People (reasonably) focused on acetyl choline because one of the most prominent early symptoms of Alzheimer's is memory loss.

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3. sgcox on February 3, 2010 9:39 AM writes...

Dimebon is available over the counter and without prescription in Russia and may be in some other countries. If it is indeed get proved to be effective for Alzheimer, how can you stop people buying the approved and available anti-allergy pill and use it instead of the exclusive Pfizer medicine ??

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4. starless on February 3, 2010 9:48 AM writes...

sgcox, Dimebon is not used as anti-allergic since 1990's. And Russian approval laws are very different from US laws, but that's another story. Briefly, if you want to approve a drug in Russia, you must show that this drug is safe, but proof of effectiveness can be rather weak.

Derek, the town where IPAC is located is called not Chemogolovka but Chernogolovka. Funny typo, because first can be translated as "chemical head" and the true name as "black head"

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5. Andy on February 3, 2010 10:41 AM writes...

Glad you fixed that typo, it's much better now with everything struck through! :P

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6. milkshake on February 3, 2010 11:11 AM writes...

cognitive enhancement of dimebon can be elusive in countries where a typical shot of vodka measures 100 grams

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7. Derek Lowe on February 3, 2010 11:31 AM writes...

Yeah, all strike-through is my new style. Six months, everyone'll be doing it. Aargh.

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8. Sili on February 3, 2010 1:57 PM writes...

Yeah, all strike-through is my new style. Six months, everyone'll be doing it. Aargh.
Nah. Phil Plait has been using it since forever.

Speaking CNS(?) Neurosearch just doubled their shareprice announcing news from phase III trials on something against Huntingdon's Chorea.

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9. Evorich on February 4, 2010 8:24 AM writes...

It's clear that the only thing that will genuinely treat Alzheimer's is a cocktail of therapies; i.e. an anti-inflammatory/anti-histimine, a beta-secretase blocker, an APP aggregation blocker, and a neuronal stimulator/ache blocker. What would FDA approval for taking all these together look like??

Btw - Russian names are often spelt wrong simply because they themselves find it hard to translate from their alphabet to ours. They have letters we don't have and can't even pronounce! Every spelling in our alphabet is wrong to them!

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10. David Harmon on February 25, 2010 2:55 PM writes...

I chalk that up to the "rn" looking very much like an "m",

FYI/A, this is the ur-example of keming: "the result of improper kerning."

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