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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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April 6, 2010

A Brief and Not At All Intemperate Evaluation of the Current Literature

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Posted by Derek

In keeping with my Modest Literature Proposal from earlier this year, I would like to briefly point out a Journal of Medicinal Chemistry paper on potential Alzheimer's therapies. Whose lead compound has a nine-carbon alkyl chain in the middle of it. And weighs 491. And has two quaternary nitrogens. Which structural features will, in all likelihood, lead to said compound demonstrating roughly this amount of blood-brain barrier penetration, assuming it reaches sufficient blood levels to get that far. That is all.

Comments (22) + TrackBacks (0) | Category: Alzheimer's Disease | Pharmacokinetics | The Scientific Literature


1. You're Pfizered on April 6, 2010 12:19 PM writes...

Accepted without revisions as well.

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2. Hap on April 6, 2010 12:19 PM writes...

Does it get demethylated somewhere (could this be a prodrug for something that could get into the brain)? Would it help if it did?

At least there aren't any quinones.

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3. J-bone on April 6, 2010 12:46 PM writes...

That's a great Youtube link. That is all.

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4. Sili on April 6, 2010 12:47 PM writes...

My dear dr Lowe.

You really do have a way with words.

(Now, write that book.)

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5. Smokey on April 6, 2010 1:47 PM writes...

That is on old 16 wheeled Lipinski truck. Maybe if they had 2 dump trucks linked together it would easily get through the barrier.

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6. Rogi on April 6, 2010 1:57 PM writes...

If it doesn't work on Alzheimer's, there is a good chance that the double quat would make a good disinfective additive to Lysol or a hand sanitizer.

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7. milkshake on April 6, 2010 2:53 PM writes...

maybe they can make tetrahydrocarboline version of this stuff, in hopes that it will get taken up by some transport protein and then oxidized by MAOs to the target molecule, just like it happens with MPTP to MPP+ comnversion

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8. milkshake on April 6, 2010 2:56 PM writes...

by the way, the tetrahydrocarboline version of this monster would look a lot like Dimebon

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9. Jose on April 6, 2010 3:20 PM writes...

Ah, yes, the joys (and savants) of academic med chem!

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10. partial agonist on April 6, 2010 3:39 PM writes...

That paper does no more to represent the mindset of academia than is would represent the mindset of all Germans, or all scientists named Yvonne.

If this academic med chemist had been a reviewer, I would have said show me the %$$#$ PK data, including BBB penetration. Without that, it simply isn't med chem but an exercise in compound-making and wishful thinking. Without that, it shouldn't even be a poster at a regional ACS meeting (well, if the authors were from the US... the German Chemical Society perhaps?)

To be fair, since I worked in big and medium pharma for 12 years, this type of mindset would never exist there. It also doesn't exist in any half-decent academic group nowadays either.

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11. Jose on April 6, 2010 4:16 PM writes...

"Without that, it simply isn't med chem but an exercise in compound-making and wishful thinking."

This is precisely my point. Why then, does it make it into the flagship, med chem journal of record? The paper is simply nonsense from any reasonable human systems biology view, especially considering the indication, which is the core of med chem!

That's what I find so naive and sad about so many papers like this- do they even realize how astonishingly and staggeringly far from biological reality this is? Maybe the SAR just took them here, and they decided to at least salvage a pub from it?

That said, my apologies for tarring a whole range of academics.

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12. academic on April 6, 2010 5:42 PM writes...

@jose and partial agonist
I agree with you (and others) that it is dumb to look at compounds that you know will never be able to make it as drugs.
But, in the defense of academics, do we really have to have the resources of a biotech company before we are able to get an article in J. Med. Chem.?
If we only have IC50 data, for example, does that mean we can only publish in Bioorg. Med. Chem. Lett.?

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13. Hap on April 6, 2010 6:08 PM writes...

I would figure that most med chem depts. have animal access (it wouldn't be helpful if there isn't sufficient money in a med chem grant to see how something actually behave in living things), but even if they don't, designing something with the intent of administering it to living things ought to act as a "sanity test" - if your lead can't get into animals on a bet, then you shouldn't be claiming med chem utility for it. It might be a useful tool or a way of understanding the underlying biology, but if it can't possibly be a medicine, then it probably shouldn't be in a medchem journal.

If the only likely consequences of a med chem paper are to cause med chemists to spit-take all over their monitors and wonder what the reviewers were doing while reading the paper, then at the least the paper's in the wrong journal.

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14. Pete on April 6, 2010 8:57 PM writes...

I have a theory that the only thing that keeps these sorts of compounds in solution is the solvation energy of the counterions. You may want to take a look at compounnds 14 and 15 in the Baell/Holloway PAINS article:

BTW, have you seen what has just followed the dications into JMC ASAP:

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15. doctorpat on April 6, 2010 10:11 PM writes...

As a non-chemist who worked in the non-pharma health field... is it completely ridiculous to directly inject a compound into the brain?

Sure that's a major invasive procedure, but this is Alzheimer's, which is effectively fatal.

To go all science fiction on you, an implanted dosage pump that mechanically bypassed all those blood-level, blood-brain-barrier issues would be a TOTALLY acceptable price to keep a person's brain functional.

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16. MoD on April 7, 2010 12:07 AM writes...

New strategy emerging for Alzheimer's treatment??? If the compound (drug?) actually gets to the brain, maybe it can form its own deposit which will then block the formation of amyloid plaques.

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17. Dr Van Nostrand on April 7, 2010 5:49 AM writes...

What's the estimated Hill slope of the dose-response curve in the graphical abstract? Looks pretty steep to me...I hope they even got the mechanism of action right...

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18. Wavefunction on April 7, 2010 8:56 AM writes...

-Maybe the SAR just took them here, and they decided to at least salvage a pub from it?

Bingo. If not a drug, at least a paper.

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19. Vader on April 7, 2010 9:15 AM writes...

Geez, Derek. Give me some warning. My employer's NetNanny flagged that as a pornographic video.

I suppose I should have guessed that a video having something to do with penetration would be a problem ...

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20. Derek Lowe on April 7, 2010 9:23 AM writes...

Vader, I hope you're joking, 'cause if you're not, your interet firewall is being a bit touchy. Actually, not every computer at my workplace is playing it, either, but that just seems to be a general "YouTube = lost productivity" rule in the database. At any rate, there's nothing stimulating at all in that clip, unless maybe you're J. G. Ballard.

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21. Evorich on April 7, 2010 2:17 PM writes...

Well yes @academic et al, the point is that this is the Journal of Medicinal Chemistry i.e. chemistry that might relate to a medicine at some point. It is not the Journal of stuff-we-found-that-made-the-graph-change-shape Chemistry.

But actually if you run this compound through a BBB model it . . . okay yeah - see the video!

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22. Liz on April 8, 2010 12:58 AM writes...

I had to log in to youtube in order to view it because it said that the video could be inappropriate for those under 18.

Oh and that made me laugh out loud, even though I had an idea of what was coming.

Short but sweet for sure.

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