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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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November 2, 2011

Tiny, Tiny Molecules for MS

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Posted by Derek

What is the deal with multiple sclerosis and small off-the-shelf molecules? Last year I wrote about Ampyra, which is 4-aminopyridine. Now Biogen is showing what looks like good results with BG-12, which is. . .dimethyl fumarate. See the Haystack blog for more. The same comments I made earlier about Ampyra's intellectual property situation apply here - it's just interesting to see that Biogen has a hand in both of these. What's next? Toluene?

Comments (38) + TrackBacks (0) | Category: The Central Nervous System


1. opsomath on November 2, 2011 8:14 AM writes...

From the 4-aminopyridine comment thread:

"Derek, do you think you will have a similar post when Biogen launches dimethylfumarate, currently in Phase III. How many medicinal chemists does it take to esterify fumaric acid. It's not even the ethyl ester for pity sake!"

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2. PJ Hansen on November 2, 2011 8:24 AM writes...

..and it protects furniture against mold. Sounds like Shimmer. "It's a floor wax AND a dessert topping."

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3. PJ Hansen on November 2, 2011 8:25 AM writes...

..and it protects furniture against mold. Sounds like Shimmer. "It's a floor wax AND a dessert topping."

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4. jlehmann on November 2, 2011 8:37 AM writes...

Derek, if I am not mistaken both 4-aminopyridine and dimethyl fumerate are chemically reactive molecules that may deplete glutathione and evoke an anti-oxidant response. The concept is similar to what is coined hormesis: "generally favorable biological responses to low exposures of toxins or stressors". Toluene diisocyanate might be a better bet.

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5. David Formerly Known as a Chemist on November 2, 2011 8:43 AM writes...

It's refreshing to see such a simple molecule potentially possess such exciting utility. If a medicinal chemist looked at the structure of salicylic acid today, would they ever believe that could represent one of the most useful medications in human history? It's humbling.

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6. luysii on November 2, 2011 9:10 AM writes...

#5 Salicylic acid isn't that useful but acetyl salicylic acid is (probably because it's an acetylating agent). Since one of the (many) controls of gene transcription is the extent to which the histones about which DNA is wrapped around are acetylated, we are far from knowing just how aspirin works, although in the early arrogant days, we all 'knew' exactly it worked (by inhibiting cyclo-oxygenase).

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7. enzgrrl on November 2, 2011 9:34 AM writes...


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8. Curious Wavefunction on November 2, 2011 9:39 AM writes...

How about metformin, the billion dollar diabetes drug? Something that no chemist in her right mind would have touched.

luysii: Given the simple structure of aspirin and the reactivity of the acetyl group, it would be surprising if it did *not* hit anything other than Cox. (By the way is there actual evidence indicating that aspirin may be involved in histone acetylation? If so, I would be interested in references)

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9. luysii on November 2, 2011 10:07 AM writes...

#8 While it is not surprising to you (presently) that aspirin acetylates many proteins in the cell, let me assure you that in the 70s and 80s when aspirin was coming into use as a preventitive for strokes, MIs etc. etc., it seemed completely clear to the medical powers that be, that the mechanism of aspirin action for this effect was COX inhibition. Their certainty was appalling. I took to making lists of the other things aspirin did as a way of arguing with these people.

This was not an academic exercise, as people argued that the correct dose of aspirin was whatever inhibited COX, rather than doing dose response studies to find out what the best dose actually was. The study with the greatest reduction in stroke rate that I could find used 1300 milligrams/day (2 adult aspirins twice a day), but people used far less because of the COX work. I got into all sorts of arguments because of this. Typical of medicine at the time, but hopefully at present.

For a study on what proteins aspirin acetylates see Int. J. Oncol. vol. 39 pp. 1273 - 1273 '11 -- the list is quite long and includes histones.

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10. John Schilling on November 2, 2011 10:41 AM writes...

Xenon seems to be used at least experimentally, and successfully, as an anaesthetic and a brain-injury neuroprotectant. That's going to be hard to beat for simplest medically useful molecule...

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11. sgcox on November 2, 2011 10:51 AM writes...

luysii, how does that paper proves that aspirin acetylates anything? It only showes the increase of lysine acetylation in cells upon aspirin exposure. Most likely mechanism is the HDAC inhibition, imho. Or it can be stimulation of HATs activity. But does anybody showed the direct transfer of aspirin' acetyl to protein lysines ??

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12. anchor on November 2, 2011 11:35 AM writes...

Reminds me of the chloroacetic acid for the treatment of cancer.

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13. MTK on November 2, 2011 11:48 AM writes...

If you guys want me to make you some isotope labeled aspirin, I'll glad you provide a quote. :)

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14. simpl on November 2, 2011 11:49 AM writes...

Today's molecule in the news for slowing the aging process is acetylcysteine

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15. cynical1 on November 2, 2011 12:33 PM writes...

@ opsomath #1:

Yeah, that was me that said that. So I'll go ahead and fess up that I was wrong on that one. I would have bet money that it wouldn't work. I have no clue how it works either. My best (pathetic) guess is that it's a Michael acceptor in some enzymatic pathway yet to be discovered but I never invested too much of my forebrain in trying to figure it out either. Maybe small doses of methanol from methyl acetate would work as well. What do I know?

With that said, it's a pittance to Ocrelizumab which has demonstrated a 90% reduction in new lesions in a decent size phase II study from Roche. (Ya gotta love those anti-CD20 antibodies!). At least that one I did predict.

The saddest thing for me is that my wife almost died of MS related seizures a few weeks ago in the hospital and is now recovering (hopefully) temporarily in a nursing home until I can bring her home. There's nothing in the clinic for secondary progressive and we both know where this is headed. She's 52 years old.

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16. luysii on November 2, 2011 12:33 PM writes...

# 11 -- sgcox -- Quite possibly, you're correct, although your proposed mechanism involves an extra step (or more) BUT, if the net effect of aspirin is to increase histone acetylation, the mechanism by which it does so is irrelevant for the effect it has on cells and organisms, which was my primary concern as an M. D.

I'm not sure when the histone code actually came into existence, but, it wasn't in the air in the 70's and 80's.

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17. Steve on November 2, 2011 1:03 PM writes...

another small molecule with interesting pharmacology is dichloroacetic acid. It is used in infant open heart surgery to protect against ischemia activates PDH

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18. luysii on November 2, 2011 1:45 PM writes...

#15 Cynical1 -- Do NOT screw around with methanol. The body makes formaldehyde out of it, and it's why alcoholics drinking Sterno go blind (if they don't die).

(Epileptic) seizures in MS are as rare as rocking horse manure. Are you sure your wife has been correctly diagnosed?

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19. luysii on November 2, 2011 1:48 PM writes...

#15 Cynical1 -- Do NOT screw around with methanol. The body makes formaldehyde out of it, and it's why alcoholics drinking Sterno go blind (if they don't die).

(Epileptic) seizures in MS are as rare as rocking horse manure. Are you sure your wife has been correctly diagnosed?

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20. cynical1 on November 2, 2011 2:46 PM writes...

@luysii - I know what methanol is metabolized to. I'm a medicinal chemist. I'm not some yahoo. I was being sarcastic. But I would guess that patients might be getting exposed to it with 240 mgs of a dimethyl ester dosed three times a day. Or am I just stupid in making such an assumption?

And my wife's neurologist, who holds an MD/PhD from Washington University in St. Louis, has told me that I know more about MS than anyone he's ever met. He routinely asks me what I think of the drugs in the trials that they participate in. So yes, I am sure she has MS. She has met all the McDonald diagnostic criteria ect. through multiple clinical criteria. He's sure she has MS. Everyone's sure she has MS (except you). And seizures in MS are 8-10 times above the general background incidence and I led a depraved childhood living overseas in Africa so I never had a rocking horse so I can't speak to how often little children crap out when using one. But I can understand the results from the EEG and the ongoing background seizure activity.

But when you sit there and watch her wetting herself, her whole body shaking and blood coming out of her mouth while she's biting her tongue for almost 3 minutes with her eyes rolled up in her head, while you're on the phone with 911, and you suddenly leap to the conclusion that, holy crap, she's having a seizure. I think I saw it on ER once. We put a DNR on her in the ICU. Does that suffice? I think that I'll keep with my own training and that of the largest neurology clinic in the Southeastern US.

There's a lot more manure that comes from getting on one's high horse, actually. I've found a fair amount of that from doctors and neurologists, in particular, over the years. They tend to be a pretty arrogant lot being the most difficult specialty and all that. I guess it goes to their head or something. It's really sort of annoying.

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21. Jumbo on November 2, 2011 3:04 PM writes...

Let's not forget Lithium.

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22. Dickweed Jones on November 2, 2011 4:02 PM writes...

@15 Very sorry to hear your sad story. I remain skeptical about fumarate, but I hope I'm wrong and it does give her some relief.

@14 N-acetylcysteine is already a drug

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23. JH on November 2, 2011 4:44 PM writes...

Dimethyl fumarate is also a vicious allergic sensitizer. I've read of a case where a manufacturer of shoes in china had applied it to prevent mould growth, giving the unfortunate end users terrible skin problems. I wouldn't have expected that out of such a simple compound. Look it up on wikipedia.

And about aspirin being capable of acetylation. In aqueous solution the anion actually exists in equilibrium with the phenolate anion of acetic salicylic anhydride and an orthoester type oxygen anion. There was a paper in Tet. Lett. some months ago. As carbohydrate chemists well know, funny things happen when you have acetyls so near to hydroxyl groups. I wouldn't be surprised if it really did acetylate stuff in vivo.

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24. Anonymous on November 2, 2011 6:02 PM writes...

Apparently dimethyl fumarate reacts with reduced glutathione (GSH). What about liver toxicity or oxidative stress in cells since you may be depleting the reduced form of GSH and upsetting the equilibrium between reduced GSH and oxidized GSH (ie: the disulfide).

We all know the consequences of depleting GSH...the toxic quinone imine metabolite (michael acceptor) of acetaminophen is a classic example.

I'd like to see the results of an ascending dose study in rodents comparing dimethyl fumarate with acetaminophen...should be quite interesting and informative!!

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25. Canageek on November 2, 2011 7:05 PM writes...

#10: Xenon? Really? Doesn't a molecule have to, you know, react, to get involved in the body? Wouldn't the conditions needed to get xenon to do anything be rather lethal? Heck, considering that most of the reactants that you can make xenon compounds with also react rather violently with water, how would the body do anything with xenon?

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26. Canageek on November 2, 2011 7:56 PM writes...

#10: Xenon? Really? Doesn't a molecule have to, you know, react, to get involved in the body? Wouldn't the conditions needed to get xenon to do anything be rather lethal? Heck, considering that most of the reactants that you can make xenon compounds with also react rather violently with water, how would the body do anything with xenon?

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27. Anonymous on November 2, 2011 8:19 PM writes...

4-aminopyridine is a bird control agent as Derek pointed out. Given the pharmacokinetics of this substance in humans (see below) coupled with dispensing issues, it it inevitable that this substance will make its way into the environment / water supply. Given the toxicity to invertabrates/mammals, it's another disaster waiting to happen.....

Elimination Route

Following oral administration, 95.9% of a dalfampridine dose is eliminated in urine and 0.5% is eliminated in feces.1

The majority of the dose is eliminated in urine (90.3%) as unchanged dalfampridine;1 4.3% is eliminated as 3-hydroxy-4-aminopyridine and 2.6% is eliminated as 3-hydroxy-4-aminopyridine sulfate.1

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28. barry on November 2, 2011 8:38 PM writes...

re: #26

if by "react" you mean covalently, no, only a tiny minority of drugs (beta lactams, proton pump blockers, aspirin...) react covalently with their targets. Many are excreted unchanged entirely. Even some that look reactive to a chemist (e.g. cyclopropane) is breathed out unchanged after having its anaesthetic effect.

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29. sepisp on November 3, 2011 6:46 AM writes...

#14: The English professor is not the first. Biohit has already commercialized L-cysteine, as Acetium, as an anticarcinogen for achlorhydria (low stomach acid, occurs as is or when using PPIs). As for mechanism, it's simply a nucleophile that attacks carcinogenic acetaldehyde produced by microbes in the achlorhydric stomach.

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30. Hap on November 3, 2011 10:21 AM writes...

25: Xenon and its compounds are really different (considering how long it took to actually prepare xenon compounds, that should not really be a surprise) - xenon's oxidation potential is high, so its compounds are really strong oxidants, while xenon itself is not. I think xenon is administered as a gas, though it can also (I think) be administered with a cavitand for NMR (as a solution in ?)

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31. simpl re acetylcysteine on November 3, 2011 11:16 AM writes...

#22, #29
I was aware that acetylcysteine is a drug, for stuffy noses, and a food supplement(cheaper, low side-effects). I hadn't realised before that it was a cure-all, and successor to vitamin C.
Regarding the mechanism as an anticarcinogen for achlorhydria, does that imply that I would also improve my lifespan if I stop taking Nexium?

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32. newnickname on November 3, 2011 2:10 PM writes...

Tiny hydrazine sulfate for cancer? (Except it doesn't work.)

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33. Dickweed Jones on November 3, 2011 2:46 PM writes...

@31 NAC is the antidote for acetaminophen poisoning.

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34. Guppy on November 3, 2011 3:44 PM writes...


Why would it have to react with anything? It takes up space, it has a shape, it is subject to Van Der Waals forces. That's plenty to interact with a biological system.

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35. nonchemist on November 4, 2011 2:20 AM writes...

It has to react with something because that is what every medicinal chemist (at our company) seems to say when they see activity they cannot explain in a molecule they don't like the look of...

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36. sepisp on November 4, 2011 8:20 AM writes...

#35: Xenon cannot react in physiological conditions, it's a noble gas and completely nonreactive. But, it can dissolve into human tissue, change the conformation of proteins and alter permeability of membranes without any chemical reaction occurring. In fact Wikipedia has references to this effect.

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37. nate on November 4, 2011 11:59 AM writes...

Fomepizole (ADH inhibitor) for EG and MeOH toxic

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38. Benbisley on November 6, 2011 10:13 AM writes...

#20 Cynical1

My wife also has SPMS. She was written off by a neurologist in a five minute consultation. Please have a look at these pages:

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