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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 11, 2002

Thalidomide in the Mirror

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Posted by Derek

Whenever the topic of drug safety trials comes up, there's likely to be a mention of thalidomide, and rightly so. As with any such event, you find various levels of knowledge among different people, even among those who believe that they have the real information.

Stipulating that we're ignoring the (substantial) fraction of the public that's never heard of it, the next group to clear out of the way are those who believe that the drug caused problems in the US. That's the usual point of articles that mention it, actually - that the FDA didn't approve it for use here, while European authorities did. (This theme repeated itself more than once, unfortunately - I'll talk about another example in a few days.)

Now we get to some really persistent mistakes. Most folks who know about drug discovery will tell you about the lessons of thalidomide as they relate to the chirality of drugs. And most of them have it wrong. The amount of misinformation on this subject is so great - just look on the web - that it'll probably never go away.

(Chirality, for those outside the field, is basically "handedness." Nonchiral objects (like balls) can be switched around freely when they interact with chiral ones - there's no right and left, and no way to mismatch them. Chiral objects, though, (like right and left shoes) aren't superimposable, and you can't substitute one type for another. On a molecular level, living creatures are chiral, because the amino acids and sugars in their cells are - see my March 19 post. Thus, right-handed and left-handed forms of chiral drugs often have quite different effects.)

Thalidomide has a chiral carbon atom, in the middle of what (by present-day standards) is a rather odd structure with two imides in it, which is two more than most folks would like to see in their drug candidates. Like almost all drugs from that era, the compound was sold as a 1-1 mixture of the right- and left-handed forms (enantiomers, to us chemists.) The mistake is the oft-repeated notion that the terrible teratogenic effects are only found in one of the two isomers - had the compound been sold as the single active enantiomer, the story has it, all the birth defects could have been avoided.

Wrong. An article in the October issue of Nature Reviews: Drug Discovery (see page 757) helps to set the record straight. There are two problems with the common wisdom, one of which is that the in vivo studies don't bear it out. It's true that one enantiomer is more teratogenic in mice than the other one, but this work involved high doses, because mice just aren't very sensitive to the compound. Humans are, though, unfortunately, and both enantiomers are equally bad in rabbits, who are similarly susceptible.

The second problem shows that the mouse results are actually a surprise. The chiral center in thalidomide isn't stable under many in vivo conditions, and the compound can be converted to a mixture of both forms no matter which one you start with. In most species, you wouldn't be able to tell if there was a different toxic potential in the two enantiomers at all, because you'd never be able to dose only one.

Interesting, the compound has made a comeback in recent years as a treatment for some kinds of leprosy, and it's being investigated in cancer and several other diseases. It has some unique properties. A big challenge, though, is making sure that no woman who's even possibly going to get pregnant gets near the stuff. . .

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