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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: derekb.lowe@gmail.com Twitter: Dereklowe

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July 10, 2014

A Drug Candidate from NCATS

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Posted by Derek

I've written several times about the NIH's NCATS program, their foray into "translational medicine". Now comes this press release that the first compound from this effort has been picked up for development by a biopharma company.

The company is AesRx (recently acquired by Baxter), and the compound is AES-103. This came from the rare-disease part of the initiative, and the compound is targeting sickle cell anemia - from what I've seen, it appears to have come out of a phenotypic screening effort to identify anti-sickling agents. It appears to work by stabilizing the mutant hemoglobin into a form where it can't polymerize, which is the molecular-level problem underlying the sickle-cell phenotype. For those who don't know the history behind it, Linus Pauling and co-workers were among the first to establish that a mutation in the hemoglobin protein was the key factor. Pauling coined the term "molecular disease" to describe it, and should be considered one of the founding fathers of molecular biology for that accomplishment, among others.

So what's AES-103? Well, you'll probably be surprised: it's hydroxymethyl furfural, which I would not have put high on my list of things to screen. That page says that the NIH screened "over 700 compounds" for this effort, which I hope is a typo, because that's an insanely small number. I would have thought that detecting the inhibition of sickling would be something that could be automated. If you were only screening 700 compounds, would this be one of them?

For those outside the business, I base that opinion on several things. Furans in general do not have a happy history in drug development. They're too electron-rich to play well in vivo, for the most part. This one does have an electron-withdrawing aldehyde on it, but aldehydes have their own problems. They're fairly reactive, and they tend to have poor pharmacokinetics. Aldehydes are, for example, well-known as protease inhibitors in vitro, but most attempts to develop them as drugs have ended in failure. And the only thing that's left on the molecule, that hydroxymethyl, is problematic, too. Having a group like that next to an aromatic ring has also traditionally been an invitation to trouble - they tend to get oxidized pretty quickly. So overall, no, I wouldn't have bet on this compound. There must be a story about why it was tested, and I'd certainly like to know what it is.

But for all I know, those very properties are what are making it work. It may well be reacting with some residue on hemoglobin and stabilizing its structure in that way. The compound went into Phase I in 2011, and into Phase II last year, so it does have real clinical data backing it up at this point, and real clinical data can shut me right up. The main worry I'd have at this point is idiosyncratic tox in Phase III, which is always a worry, and more so, I'd think, with a compound that looks like this. We'll see how it goes.

Comments (19) + TrackBacks (0) | Category: Clinical Trials | Drug Development


COMMENTS

1. A Nonny Mouse on July 10, 2014 9:11 AM writes...

We had a programme at Wellcome (UK) in the old days for sickle cell. These compounds were also aldehydes (2-hydroxy benzaldehydes)which formed a very strong schiffs base with an amine. There was also an acid hanging off of a chain which bound with another part of the haemoglobin. These 2 interactions held the molecule + oxygen together for longer. The compounds worked very well on the in house volunteers that it was tried on.

The major problem was with the clinical trials in the US; the company eventually gave up trying as the patient population consistently failed to turn up for appointments

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2. A Nonny Mouse on July 10, 2014 9:13 AM writes...

PS. All of the "molecular modeling" was actually done with physical models.

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3. John Wayne on July 10, 2014 9:21 AM writes...

I worked on some furfurals about 20 years ago at Pfizer (before it became Big Blue). This furfural is probably okay, but some very close derivatives are crazy light sensitive.

It will be interesting to see how this goes. I've been taught that you should look at the data, then the structure, before deciding what to do. Some success here (combined with the power of fumarates) will teach us what we don't know about low molecular weight drugs; alternatively, it will teach us how to not get crushed in phase 3.

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4. C Wood on July 10, 2014 9:51 AM writes...

Furfural and its brethren are, as mentioned above, unstable as all get-out, and HMF specifically is quite unstable. We have been working with generating furfural from biomass, and the biggest challenge is keeping it around after you make it (it likes to polymerize with itself and anything else handy), and HMF has an even worse reputation from that end of things. It would be interesting to know what they are doing to stabilize it, as furfural will polymerize with itself just sitting on the lab bench.

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5. alig on July 10, 2014 9:53 AM writes...

Leads to higher blood oxygen content in healthy volunteers. Wonder if it is being used at the tour de France?

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6. milkshake on July 10, 2014 10:43 AM writes...

HMF oral absorption and metabolism has been already studied in a great detail. HMF is ubiquitous in baked foods, it has been even used as a flavoring agent. You have to weight HMF against the nastiness of currently used sickle-cell anemia drugs (N-hydroxyurea)

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7. ErrHuman on July 10, 2014 11:05 AM writes...

Can't remember which review it was in, but its been estimated ingest an about 50 mg of HMF every day from various foods. Carbohydrates + heat gets you HMF every time.

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8. samadamsthedog on July 10, 2014 11:08 AM writes...

But if this compound stabilizes the oxygen-binding form of hemoglobin, won't the hemoglobin have trouble releasing the oxygen to myoglobin once it's transported to muscle cells? This does not sound good for tour de France riders.

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9. Poul-Henning Kamp on July 10, 2014 11:29 AM writes...

The Trial 1 description makes it sound like something we'll see in Tour de France real soon.

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10. Poul-Henning Kamp on July 10, 2014 11:31 AM writes...

The Trial 1 description makes it sound like something we'll see in Tour de France real soon.

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11. Anonymous on July 10, 2014 12:00 PM writes...

How does the NIH NCATS program obtain compounds to conduct screening? Do they just buy commercially available ones and upon a hit, declare a lead molecule?

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12. milkshake on July 10, 2014 12:15 PM writes...

in the clinic they are testing MHF in doses of several grams a day (without observing significant adverse reactions)... Thats a lot. If this thing drug acts as a hemoglobin covalent modifying agent, I wonder what else gets modified, and what delayed effect may have few years later...

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13. Puff the mutant dragon on July 10, 2014 12:20 PM writes...

Yeah, if I were me I would be very worried about chronic tox/long-term effects. But then I guess as pointed out above this is all relative to the nastiness of n-hydroxyurea.

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14. diverdude on July 10, 2014 1:06 PM writes...

@1 Interesting, I helped run the clinical pharmacology programme for that compound and the biggest problem was not patients not turning up for the clinical studies, it was the big immune response to the hapten formed by the compound leading to all sorts of AEs.

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15. diverdude on July 10, 2014 1:06 PM writes...

@1 Interesting, I helped run the clinical pharmacology programme for that compound and the biggest problem was not patients not turning up for the clinical studies, it was the big immune response to the hapten formed by the compound leading to all sorts of AEs.

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16. A Nonny Mouse on July 11, 2014 9:41 AM writes...

# 14 15

I was working in the lab with the discoverers of this (Kneen/Wates) and that is what I was told by them. Maybe they weren't giving the full picture.

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17. NoDrugsNoJobs on July 12, 2014 8:10 PM writes...

Stranger things have worked. Metforming, tecdifera (aka dimethyl fumarate). Hope it works!

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18. Anonymous on July 17, 2014 4:41 AM writes...

Too often we nitpick that we don't have the perfect molecule--not enough potency, structure groups are worrisome, etc. Well if something works it works, who cares if a molecule isn't perfect looking? Valproic acid, hormone regulating drugs, and alkylating agents are used every single day in the clinic, yet if we subscribed to theorirs of what makes a "good drug" these molecules would have been thrown away a long time ago because they would have only shown low potency in in vitro screens and their structures look dubious.

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