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Derek Lowe The 2002 Model

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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 19, 2004

Odd Elements in Drugs

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Posted by Derek

I had a question recently about why some chemical elements don't appear much in pharmaceuticals. Boron was one example - the first boron-containing drug (Velcade, from Millennium) was approved just recently.

But it hasn't been for lack of trying. Starting in the 1980s, several drug companies took a crack at boronic acids as head groups for protease inhibitors. Big, long, expensive programs against enzymes like elastase and thrombin went on year after year, but no one could get the things to quite work well enough. In vitro they ruled - a good boronic acid is about as good as an enzyme inhibitor can be. But in vivo they had their problems, with oral absorption and cell penetration leading the way.

As far as I'm aware, there's no particular tox liability for boron. Things like boric acid certainly don't have a reputation for trouble, and we don't take any special precautions with the air-stable boron compounds in the lab. It'll be hard to make any case, one way one another, based on the Velcade data, since the drug's mechanism of action (proteosome inhibition) has a lot of intrinsic toxicity anyway. (There's the anticancer field for you - there aren't many other areas where a target like that would even be considered.)

I think self-censorship is why there aren't more boron-containing structures out there. We don't spend much time looking at the compounds seriously, because everyone knows the problems with boronic acids, and no one wants to be the first to develop a different boron-containing functional group, either. "Why be the first to find a new kind of trouble?", goes the thinking. "Don't we have enough to worry about already?"

Comments (4) + TrackBacks (0) | Category: Odd Elements in Drugs | Toxicology


1. allan on April 19, 2004 10:13 PM writes...

wow, I didn't realize there were ANY boron containing drugs. Its just so...strange.

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2. Jason on April 20, 2004 3:23 PM writes...

How about fluorine/flouride? Some plants make fluoroacetic acid, a nasty dog poison. Fluoride strengthens teeth and bones by its presence in the gross matrix, but there aren't any fluoride receptors (I don't think). So it's somewhat obscure. It occurs more frequently than I'd expect considering its marginal significance in biochemistry. (Flonase, Prozac,...) Is that a defense against liver enzymes?

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3. Derek Lowe on April 20, 2004 9:31 PM writes...

You're right that fluorine isn't very biochemically significant (too high a bond energy to be worth it, apparently). Fluoroacetic acid is one of the weird exceptions (and it's not just a dog poison, it's pretty much an everything poison).

But fluorine is definitely our friend in medicinal chemistry. It doesn't take up that much more room than a hydrogen atom, but changes the properties of your molecule pretty drastically. I wish there were more elements like that!

Your guess is correct about the liver enzymes. There are any number of fluorinated phenyls out there in the drug world, and in almost all of them, it's there to block a position that otherwise would be oxidized by a cytochrome enzyme in the liver.

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4. Biomaven on April 30, 2004 4:33 PM writes...

Another boron-containing drug, currently in Phase II trials for cancer, is PT-100 from Point Therapeutics:


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