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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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In the Pipeline

« All Those Worthless Papers | Main | What To Do With The Not-Quite-Worthless »

June 24, 2010

Fungal Structures to the Rescue

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Posted by Derek

From the Wall Street Journal, here's the history of the Novartis compound fingolimod, from its intellectual origins as a cicada fungus extract to today, when it might become the first oral medication for multiple sclerosis.

If fingolimod makes it, it'll also be the first drug I'm aware of that has a flippin' n-octyl chain hanging off it - a flagrant violation of everything that a medicinal chemist learns in their first month on the job. Hydrophobic bulk, metabolism bait, entropic penalty - well, there it is. I'm not suggesting that we all go out and slap pennzoilane and crisco-cene side chains on our lead drug candidates, but it's worth remembering that the race is not always to the swift, nor the battle to the strong.

Comments (29) + TrackBacks (0) | Category: Drug Development


1. anchor on June 24, 2010 11:50 AM writes...

Derek : Good story and even better was the results of clinical trials from Avid Radiopharmaceuticals. A promise for detection of Alzheimer's disease is on the horizon from this small start up. They did so by PET scan, and involved tagging the dye molecule with F-18!

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2. processchemist on June 24, 2010 12:01 PM writes...

About long alkyls hanging, orlistat probably detains the record.

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3. anon the II on June 24, 2010 12:06 PM writes...

This is all a little curious. I remember from my first job that this myriocin compound was kicking around in the company (Ayerst) and nobody really knew what to do with it. The level of interest rose a bit after FK-506 caused a rise in interest of another old compound kicking around (for 15 yr.) that nobody knew what to do with called rapamycin.

The WSJ article and the wikipedia link don't seem to go back to the guy who started this work so I thought I'd provide a link.

Suren passed away in January, 2003.

You can find a bit on the early work by Googling "myriocin Ayerst".

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4. anon the II on June 24, 2010 12:15 PM writes...

One other thing. If you dig into the past on rapamycin and myriocin, Derek's comment "that the race is not always to the swift, nor the battle to the strong" seems especially true.

The current model of pharmaceutical discovery will largely eliminate this route of discovery in the future.

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5. Al Osteric on June 24, 2010 12:21 PM writes...

I know this isn't really the same thing, but there are topical antibiotics like benzalkonium chloride that have long alkyl chains. Obviously they don't have to go through metabolism, and so aren't directly comparable. They also function by a completely different mechanism but they do have somewhat similar (simple) structures. It never ceases to amaze me the number of drugs that get approved despite such obvious and substantial differences from that which we think of as "drug-like" molecules.

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6. yep on June 24, 2010 12:23 PM writes...

Anti-infectives will frequently side-step these medicinal chemistry rules.

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7. Design Monkey on June 24, 2010 12:32 PM writes...

Aw, it's lipid mimetical thing, octyl and stuff are normal there.

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8. Tim Leary on June 24, 2010 12:37 PM writes...

One of the wonder drugs of the late 1960s, tetrahydrocannabinol, has a n-hexyl group hanging off of the aromatic ring. I always attributed the pleasing effects it had on my brain back in those days to that greasy side chain.

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9. Anonymous on June 24, 2010 12:54 PM writes...

Follow up to 'yep', there are a number of approved antifungals and antibiotics that contain long alkyl chains: daptomycin, telavancin, micafungin, caspofungin, dalbavancin, ect. Dalbavancin is dosed twice, a week between doses, and has a 200-300 hr half-life.

There is one simple rule in drug discovery: There are no rules.

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10. Wavefunction on June 24, 2010 1:20 PM writes...

I for one am not surprised that there are structures like this which look like detergents. If I want a drug for disrupting membranes, I wouldn't shy away from such structures at all.

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11. Johnathan on June 24, 2010 2:07 PM writes...

JWH-018 (1-pentyl-3-(1-naphthoyl)indole), a synthetic CB1/CB2 receptor agonist, has a pentyl chain hanging off it. It is anecdotally reported active through the enteric route.

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12. RanDChemist on June 24, 2010 2:09 PM writes...

Don't chase the exception(s) to the "rule(s)", but also do not be afraid to follow the data.

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13. Rogi on June 24, 2010 3:09 PM writes...

Uhh.... Look at the structure of Mevacor and/or Zocaor (mevalonic acid derivative). Then look at Lipitor with it's loooonngg tether. Would you have thunk that?? Strange thing, med chem....

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14. Anonymous on June 24, 2010 3:17 PM writes...

If it looks like sphingosine...why the surprise?

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15. John on June 24, 2010 4:39 PM writes...

Low molecular weight (307 in this case) covers a multitude of sins.

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16. retread on June 24, 2010 6:01 PM writes...

Tim Leary: you probably had a bit too much of the stuff. delta9 THC has a pentyl group hanging off the benzene ring (not a hexyl).

It took much longer for the cannabinoid receptors to be found than those of the other neurotransmitters, because the ligands are so lipid soluble they dissolve in every membrane they're exposed to (unlike norepinephrine with its 3 OHs and 1 amine, etc. etc.)

The 'endogenous cannabinoids (anandamide, 2arachidonyl glycerol) are mostly hydrocarbon.

That's exactly one of the creepy things about marihuana, the stuff dissolves in the lipids of the brain and probably stays there a long time. The term pot-head wasn't invented by a neuropharmacologist but it probably should have been.

Wavefunction: hydrolyze 2 arachidonyl glycerol and you do get a detergent (arachidonic acid). The enzyme FAAH (fatty acid amide hydrolyze) does exactly that to anandamide.

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17. milkshake on June 24, 2010 6:03 PM writes...

Ugliness: One needs to judge drug structures on their own merits. For example most lactam antibiotics look quite horrible because they are 1) electrophilic 2) contain thioether and hence liable to be metabolized 3) as substances they are not that chemically stable 4) often they contain multitude of polar groups and fail to meet Lipinski rules. 5) they act as irreversible inhibitors.

(The reason why they still work is that unlike many other drugs they actually do not need to get inside the cell to do their job so common druggability criterion do not apply to them. In addition the basic structural motives were selected by evolution and they are very potent.)

This arylalkyl-extended version of TRIS amine is a curious structure but its not that ugly for a stuff that is a sphingosine mimic. Kudos for a pretty simple design.

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18. LF Velez on June 24, 2010 10:38 PM writes...

I've been watching this drug since 2002, and the early articles about "vegetable wasp" Chinese medicine were starting to crop up in relation to the developmental name FTY-720. I'm thrilled it's gotten this far, and hope the side effect profile stays on the tolerable side as more patients get access to the medication.

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19. Chrispy on June 24, 2010 11:41 PM writes...

BI's new thrombin inhibitor Pradaxa has a 6 carbon ester hanging off it. Apparently this increases oral bioavailability? Is this a generalizable thing -- like, if I hang a big greasy ester off my drug can I get oral bioavailability?

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20. Anon anon anon on June 25, 2010 12:25 AM writes...

@3, Anon the II, I'm not sure I understand your comment. Why do you say "The current model of pharmaceutical discovery will largely eliminate this route of discovery in the future."?

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21. Nick K on June 25, 2010 4:28 AM writes...

This is a wonderful demonstration of the continuing importance of "pure", curiosity-driven chemistry, and why drug discovery can never be reduced to a mechanistic rules-based approach. Why then is Big Pharma cutting its natural products research?

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22. A Nonny Mouse on June 25, 2010 4:42 AM writes...

The new treatment for MS from BTG is a structured lipid with GLA in the centre and 2 C10 ester either side. Currently in PII.

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23. Anon anon anon on June 25, 2010 9:34 AM writes...

@20, Nick K:

What do you think are the major impediments to more natural product use? Why is Big Pharma cutting such research?

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24. anchor on June 25, 2010 10:09 AM writes...

Efficacy, is the name of the game with minimal AE. Who cares what the structure looks like? No company could ignore positive functional activity and FTY-720 falls in that class. Kudos to Novartis for staying with their motives!

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25. Bruce Grant on June 25, 2010 11:24 AM writes...

I can go for many a day (and have) without seeing Ecclesiastes quoted in pharma trade media. Thanks for (along with everything else you bring to this always great blog) your literacy and wit.

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26. Nick K on June 25, 2010 11:31 AM writes...

@Anon anon anon: Perhaps you can answer the question better than I can. My point is simply that Big Pharma is turning its back on a potentially rich source of drug leads, and I don't know why.

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27. g on June 25, 2010 12:20 PM writes...

Mother nature has been waging small molecule, biological warfare for billions of years. She regularly synthesizes compounds that medicinal chemists cannot even dream of.

"Nowadays, scientists generally rely on test-tube results for initial screening of experimental pharmaceutical drugs. But the Japanese group tried out all its promising drug candidates in rats, giving them skin transplants and seeing how long they survived after the resultant organ rejection."

Not fancy science, but very clever and effective. We humans think that we are much smarter than we actually are. We continually forget that some of the most dramatic advances in medicine came from seredipity.

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28. Anonymous on June 26, 2010 9:23 PM writes...

Which has done the greatest damage to our industry over the last 10 years?

1) The "rule of 5"
2) Don't think, screen, mentality
3) commoditization of medchem

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29. Dave_n on June 28, 2010 5:53 PM writes...

What is often forgotten or not even read, is that Chris Lipinski specifically identified NPs and actively transported materials as NOT obeying the Rule of 5. Methinks that people should read the original review and not the "potted precis" that is usually used!

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