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April 15, 2011
Selenium In a Drug Structure: Why Not?
You don't see too many drugs with selenium in them, that's for sure. It's one of those elements that can be used to illustrate the Paracelsian doctrine that the dose makes the poison: selenium is an essential element that's also toxic. There's no doubt at all about either of those properties; it all depends on how much of it you get.
And that's the problem with using the element in a drug molecule - the dose of many pharmaceuticals would then exceed the safe amount of selenium that a person could take in. That's especially true for whopping-dose areas like antibiotics (Home of the Horse Pill reads the sign over the door). So it's especially interesting to see that Achillion has spent some time and effort developing just that: a new antibiotic candidate whose essential feature is a selenium substitution.
No, they're not idiots. In fact, I have to salute them for having the nerve to go down this path. The key here is that the selenium in tied up in a heterocycle, a selenophene (analogous to thiophene, and not a heterocycle that very many chemists will have seen.) This keeps the element from being bioavailable, as is apparently the case with the even stranger heterocycle ebselen.
And going from a thiophene to a selenophene is not a neutral switch - in this case, it seems to have been quite helpful. The structures are in a family of topoisomerase/gyrase inhibitors that have shown a lot of promise, but have dropped out of development due to potential cardiac side effects. It's the dreaded hERG channel again, which has sunk many a development program. Binding to that ion channel can lead to long QT syndrome in some patients, and you really don't want that risk. (Neither do the regulatory agencies, which require testing of any new drug candidate for just this reason).
Switching to selenophene gave the cleanest hERG profile for Achillion's entire series of compounds, while still retaining antibacterial activity. So these selenium heterocycles are, for the adventurous, probably worth a look - they can be similar to thiophene in some situations, and not so similar in others. People are going to look at you funny if you make them, but you should never let that slow you down.
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