About this Author
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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August 21, 2014

Why Not Bromine?

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Posted by Derek

So here's a question for the medicinal chemists: how come we don't like bromoaromatics so much? I know I don't, but I have trouble putting my finger on just why. I know that there's a ligand efficiency argument to be made against them - all that weight, for one atom - but there are times when a bromine seems to be just the thing. There certainly are such structures in marketed drugs. Some of the bad feelings around them might linger from the sense that it's sort of unnatural element, as opposed to chlorine, which in the form of chloride is everywhere in living systems.

But bromide? Well, for what it's worth, there's a report that bromine may in fact be an essential element after all. That's not enough to win any arguments about putting it into your molecules - selenium's essential, too, and you don't see people cranking out the organoselenides. But here's a thought experiment: suppose you have two drug candidate structures, one with a chlorine on an aryl ring and the other with a bromine on the same position. If they have basically identical PK, selectivity, preliminary tox, and so on, which one do you choose to go on with? And why?

If you chose the chloro derivative (and I think that most medicinal chemists instinctively would, for just the same hard-to-articulate reasons we're talking about), then what split in favor of the bromo compound would be enough to make you favor it? How much more activity, PK coverage, etc. do you need to make you willing to take a chance on it instead?

Comments (38) + TrackBacks (0) | Category: Drug Development | Odd Elements in Drugs | Pharmacokinetics | Toxicology

May 6, 2013

The Medical Periodic Table

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Posted by Derek

Here's the latest "medical periodic table", courtesy of this useful review in Chemical Communications. Element symbols in white are known to be essential in man. The ones with a blue background are found in the structures of known drugs, the orange ones are used in diagnostics, and the green ones are medically useful radioisotopes. (The paper notes that titanium and tantalum are colored blue due to their use in implants).
I'm trying to figure out a couple of these. Xenon I've heard of as a diagnostic (hyperpolarized and used in MRI of lung capacity), but argon? (The supplementary material for the paper says that argon plasms has been used locally to control bleeding in the GI tract). And aren't there marketed drugs with a bromine atom in them somewhere? At any rate, the greyed-out elements end up that way through four routes, I think. Some of them (francium, and other high-atomic-number examples) are just too unstable (and thus impossible to obtain) for anything useful to be done with them. Others (uranium) are radioactive, but have not found a use that other radioisotopes haven't filled already. Then you have the "radioactive but toxic) category, the poster child of which is plutonium. (That said, I'm pretty sure that popular reports of its toxicity are exaggerated, but it still ain't vanilla pudding). Then you have the nonradioactive but toxic crowd - cadmium, mercury, beryllium and so on. (There's another question - aren't topical mercury-based antiseptics still used in some parts of the world? And if tantalum gets on the list for metal implants, what about mercury amalgam tooth fillings?) Finally, you have elements that are neither hot not poisonous, but that no one has been able to find any medical use for (scandium, niobium, hafnium). Scandium and beryllium, in fact, are my nominees for "lowest atomic-numbered elements that many people have never heard of", and because of nonsparking beryllium wrenches and the like, I think scandium might win out. I've never found a use for it myself, either. I have used a beryllium-copper wrench (they're not cheap) in a hydrogenation room.

The review goes on to detail the various classes of metal-containing drugs, most prominent of them being, naturally, the platinum anticancer agents. There are ruthenium complexes in the clinic in oncology, and some work has been done with osmium and iridium compounds. Ferrocenyl compounds have been tried several times over the years, often put in place of a phenyl ring, but none of them (as far as I know) have made it into the general pharmacopeia. What I didn't know what that titanocene dichloride has been into the clinic (but with disappointing results). And arsenic compounds have a long (though narrow) history in medicinal chemistry, but have recently made something of a comeback. The thioredoxin pathway seems to be a good fit for exotic elements - there's a gadolinium compound in development, and probably a dozen other metals have shown activity of one kind or another, both in oncology and against things like malaria parasites.

Many of these targets, though, are in sort of a "weirdo metal" category in the minds of most medicinal chemists, and that might not reflect reality very well. There's no reason why metal complexes wouldn't be able to inhibit more traditional drug targets as well, but that brings up another concern. For example, there have been several reports of rhodium, iridium, ruthenium, and osmium compounds as kinase inhibitors, but I've never quite been able to see the point of them, since you can generally get some sort of kinase inhibitor profile without getting that exotic. But what about the targets where we don't have a lot of chemical matter - protein/protein interactions, for example? Who's to say that metal-containing compounds wouldn't work there? But I doubt if that's been investigated to any extent at all - not many companies have such things in their compound collections, and it still might turn out to be a wild metallic goose chase to even look. No one knows, and I wonder how long it might be before anyone finds out.

In general, I don't think anyone has a feel for how such compounds behave in PK and tox. Actually "in general" might not even be an applicable term, since the number and types of metal complexes are so numerous. Generalization would probably be dangerous, even if our base of knowledge weren't so sparse, which sends you right back into the case-by-case wilderness. That's why a metal-containing compound, at almost any biopharma company, would be met with the sort of raised eyebrow that Mr. Spock used to give Captain Kirk. What shots these things have at becoming drugs will be in nothing-else-works areas (like oncology, or perhaps gram-negative antibiotics), or against exotic mechanisms in other diseases. And that second category, as mentioned above, will be hard to get off the ground, since almost no one tests such compounds, and you don't find what you don't test.

Comments (57) + TrackBacks (0) | Category: Cancer | Odd Elements in Drugs | Toxicology

November 7, 2012

Silicon In Drug Molecules: Not Quite There

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Posted by Derek

Now here's a subject that most medicinal chemists have thought of at one point or another: why don't I put a silicon into my compounds? Pretty much like carbon, at least when there's only one of them, right? I've done it myself - I was working on a series of compounds years ago that had a preferred t-butyl group coming off an aryl ring (not anyone's favorite, to be sure). So I made the trimethylsilyl variation, and it worked fine. We had some patent worries in that series, and I pointed out that a silicon would certainly take care of that little problem, but it was still a bit too "out there" for most people's comfort. (And to be fair, it didn't have any particular other advantages; if it had stood out more in activity, things might have been different).

I wrote a bit about this subject a few years ago here, and mentioned a company in the UK, Amedis, that was giving silicon-for-carbon a go. This idea did not, in the end, set much on fire. Amedis was bought by Paradigm Therapeutics in 2005, and a couple of years later, Paradigm was bought out by Takeda. I'm not sure if there's any remnant of the Amedis silicon era left in Takeda's innards by now; if there is, I haven't come across it.

There's a new paper on medicinally active silicon compounds, though, which might get people thinking about this whole idea once more. It's a roundup of what's known about the biological properties and behavior of these things, and will serve as a handy one-stop source for all the reported drug-like molecules in the class. As far as I can tell, the most advanced silane ever in humans has been Karenitecin, a camptothecin analogue that went into Phase III back in 2008 (and does not seem to have been heard from since).

All silicon needs is one success, and then people will take it more seriously. So far, the right combination of activity, interest, and need hasn't quite come together. If you're thinking of giving it a try, though, this new paper is the first place to start reading.

Comments (18) + TrackBacks (0) | Category: Odd Elements in Drugs

March 5, 2012

Trouble With a Boron-Containing Drug Candidate

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Posted by Derek

There have been all kinds of boronic acid-based enzyme inhibitors over the years, but they've been mostly locked in the spacious closet labeled "tool compounds". That's as opposed to drugs. After all these years, Velcade is still the only marketed boron-containing drug that I know of.

There's been a good attempt to change that in antibacterials, with the development of what's commonly referred to as "GSK '052", short for GSK2251052. That's a compound that originally came from Anacor about ten years ago, then was picked up by GlaxoSmithKline, and it's an oxaborole heterocycle that inhibits leucyl tRNA synthetase. (Here's a review on that whole idea, if you're interested).
Unfortunately, last month came word that the Phase II trial of the drug had been suspended. All that anyone's saying is that there's a "microbiological finding", which isn't too informative when it's applied to y'know, an antibacterial trial. (At least it doesn't sound like a general safety or tox problem, at any rate).

Anacor is continuing to exploit boron-containing compounds, although opinion looks divided about their prospects. I always have a sneaking fondness for odd compounds and elements, though, so I'd have to root for them just on that basis.

Comments (19) + TrackBacks (0) | Category: Infectious Diseases | Odd Elements in Drugs

April 15, 2011

Selenium In a Drug Structure: Why Not?

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Posted by Derek

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.

Comments (30) + TrackBacks (0) | Category: Infectious Diseases | Odd Elements in Drugs

May 13, 2010

You Don't See Many Names Starting with "Tellura-"

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Posted by Derek

When I wrote here about unknown compounds, using aza-steroids as examples, I apparently wasn't thinking far enough afield. I noticed this new paper on a new class of tellura-steroids. I've no doubt that they're new; probably no one has ever thought to make anything that looks quite like this before (there's one other report of a tellura-steroid from 1990). Tellurium remains an element I've never used, but after that barrage of reports from fans of hafnium the other day, I'm sort of afraid to ask what people have used this one for. . .

Comments (24) + TrackBacks (0) | Category: Chemical News | Odd Elements in Drugs

November 23, 2009

Ozonides As Drugs: What Will They Think of Next?

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Posted by Derek

You know, I often think that I have too narrow a view of what kinds of structures can go into drug molecules. (That may come as worrisome statement for some past and present colleagues of mine, who feel that my tolerances are already set a bit too wide!) But I do have limits; there are some structures that I just wouldn't make on purpose, and which I wouldn't submit for testing even if I made them by accident.

Surely ozonides fall into this category. But when I put the "Things I Won't Work With" stamp on them, at least as far as making them on scale and actually isolating them, some readers pointed out that people were investigating them for antimalarial activity. And here we are, with a new paper in J. Med. Chem. on their activity and properties.

Arterolane is the lead compound, which is in Phase III trials as a combination therapy. And it has to be one of the funkier structures ever to make it as far as Phase III, for sure, with both an ozonide and an adamantane in it. Those two, in fact, sort of cancel each other out - the steric hindrance of the adamantane is surely one of the things that makes the ozonide decide not to explode, as its smaller and more footloose chemical relatives would. You get blood levels of the stuff after oral dosing, a useful (although not especially long) half-life, and no show-stopping toxicity.
Endoperoxides are already known as antimalarials, thanks to the natural product arteminisin, which has led to two synthetic derivatives used as antimalarials. So the step to ozonides was, structurally, a small one, but must have been rather larger psychologically. And that's definitely not something to discount. I probably wouldn't have made compounds of this sort, and it's unnerving (even to me) that arterolane has gone further into the clinic than anything I've ever made. I have to congratulate the people who had the imagination to pursue these things.

Comments (18) + TrackBacks (0) | Category: Drug Development | Infectious Diseases | Odd Elements in Drugs

November 2, 2007

One For the Brave

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Posted by Derek

B-N%20structure.gifI was interested to see a recent paper in Organic Letters on a class of compounds I'd never seen before: 1,2-dihydro-1,2-azaborines. There's the structure, in case that doesn't immediately call something to mind.

These things, which are isoelectronic with benzene, were made by the Liu group at Oregon. Their method (ring-closing metathesis) for making them seems superior to the rather sparse techniques that have been available up until now, and they've prepared a number of useful and interesting intermediates. They're rather stable - even the B-H compound with an N-ethyl group, the simplest in the paper, can be run down a silica gel column. An X-ray structure shows that the ring is indeed flat, and it seems to be aromatic and delocalized.

So. . .what I'd like to know is, who's going to be the first person wild-eyed enough to put this in a drug candidate structure? Boron has a bad reputation ("boron for morons", as they say), but hey, Millennium is out there making money with Velcade, a boronic acid. I have absolutely no idea what the fate of this heterocycle is in vivo, what its toxicity might be or what it gets metabolized to (if anything). And neither do you, nor does anyone. Let's find out!

Comments (11) + TrackBacks (0) | Category: Chemical News | Odd Elements in Drugs

September 17, 2007

Arsenic, Patents, and the World

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Posted by Derek

As I was mentioning the other day, the latest issue of Nature Medicine has the details on a story that doesn’t, on the face of it, do the industry any credit. About twenty years ago, there were reports out of China that a solublized form of arsenic was very effective in treating acute promyelocytic leukemia, a rare (and fatal) form of the disease. Arsenic had been used as a folk remedy for such conditions, as it has been for many others (often with much less justification!), but its most common compounds (like arsenic trioxide) are tremendously insoluble. The Chinese authors had found a way to make that one go into solution where it could be dosed, but didn’t disclose it in their publication.

That left the door open to someone else, namely a small company called PolaRx. They found a way to do the same thing with the oxide (as far as anyone can tell), and got a patent on its use in oncology. Over years, mergers, and reshuffles, the patent finally ended up in the hands of Cephalon, who now market the soluble arsenic trioxide. However, a course of treatment costs about $50,000, which means that for many patients around the world, the drug is totally out of reach.

Even across the entire world, there aren’t that many patients for this therapy, so the price would tend to be high no matter what. It’s worth remembering that production costs are not a major factor in the pricing of most drugs. We’re not indifferent in this business to how much it costs us to make something, far from it, but we try to keep that a small part of the price. So what does set the price? What sets the price is what sets most prices in this world: what the market will bear. A drug that only treats a small number of patients every year is going to cost a lot of money, no matter what it’s made out of. A company will not market a compound unless they can use its profits to help defray the costs of all the things that don’t make it to market at all.

Cephalon is charging what their market will bear, which is their right, but their market is the health insurance organizations of the industrialized world. That’s another thing to remember – drug companies aren’t selling direct to patients most of the time. They’re selling to insurance companies, and first-world health insurance will put up with a lot of things that no one else can or will. There’s a lot of room to talk (and to complain) about this (I think it distorts pricing signals something fierce), but all the complaints have to start with the realization that this is how things are now set up. Cephalon, for its part, says that it’s open to compassionate use of its drug – that is, providing it to people in need who absolutely cannot afford it. With any luck articles like the Nature Medicine one will help to get the word out about that, and we’ll see how well they follow through.

It’s tempting to blame the patent system for this whole situation – after all, the only reason the company can charge these prices is that they’re the only ones who can sell it, right? But perversely, this might actually show the need for more use of patents rather than less. As another piece in Nature has helpfully reminded people, patents not only grant a period of exclusivity. In return for that, you have to tell people how to replicate your invention.

The alternative, in countries that don’t follow this system, is usually secrecy, and I can’t help but think that this is why the original Chinese work didn’t disclose all the details. A strong patent system eliminates a lot of trade-secret grey areas: someone owns a discovery (for a predetermined period of time), no one owns it, or everyone owns it. There’s none of this “someone owns it until someone else finds out about it” stuff.

But my guess is that the Chinese lab, being used to a trade-secret (or government-secret) culture, reflexively held back their important details. If they wanted to make sure that no one could patent anything, they would have (or at least should have) put all the information out into the public domain, where it would have been prior art against anyone attempting to file on it. (But see below - would that have helped get it through clinical trials, or not?) It’s worth noting that if a patent had been filed back in the early 1990s, the drug would not only have come to the world’s markets faster, the patent would also be much closer to expiration by now, opening up its production. The US researcher who formed PolaRx and filed the patent, Raymond Warrell (now chairman of Genta), stands up for it in the Nature Medicine article, and like it or not, he has a point, too, saying that the patent stimulated interest in the compound: "Without the patent, it would have remained a curious Chinese drug, not available to anyone else." I should note that there may well be room to argue about the validity of the patent, from prior-art concerns, but no one (as far as I know) has seen fit to challenge it.

But I can say for sure that without intellectual property protection in the US and Europe, no drug company would have touched the compound. Without industrial input, the drug would have either never reached the market at all (arsenic trials were a hard sell at the FDA), or would have likely come on more slowly. (That ticking patent clock does keep an organization moving, I can tell you). And now its success in the market has other companies working on improved versions of the therapy. This is how our world works, and (for better or worse) there's no requirement that it be aesthetically appealing.

Comments (8) + TrackBacks (0) | Category: Cancer | Drug Development | Odd Elements in Drugs | Patents and IP | Why Everyone Loves Us

January 8, 2006

My Shopping List

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Posted by Derek

Some time ago I wrote about some atoms that I wish I could use. There are still other molecular fragments that Nature has neglected to provide, though, and I'm adding to the wish list:

First off, I'd like some groups that are plain linear spacers of different lengths. Ideally, we could stick these onto carbons and heteroatoms alike. As it stands, the only commonly available group that does this is an alkyne (a carbon-carbon triple bond), and those come with their own baggage. While there are drugs that have these groups in them, they're typically treated pretty roughly by the liver enzymes. A metabolically stable alkynish thing, of variable length, would be a wonderful thing. People have made various weirdo spacers out of small bicyclic systems, true, but the synthetic routes to them are beastly, with no improvement in sight. Until we can source these things by the kilo, drug companies aren't going to be interested.

Next, I'd like some six-membered heteroaromatic rings with something other than nitrogen in them. As it is, pyridines, pyrimidines, and pyrazines are given a real workout in drug discovery programs, and we'd love to have some more options. Unfortunately, the fabric of the universe hasn't accomodated us. If you put an oxygen in there instead, it has to take on a positive charge, and that gives you a highly reactive beast called a pyrylium. It's rare that you can get one of those into a bottle, and even if you did, sending one in for biological testing would be grounds for a referral to the HR department. I see that some zanies have tried, though.

Sulfur can do the same lively thing, although I've never actually seen any of those, and there's probably a good reason for that. Varioius sorts of aromatic rings with a phosphorus atom in them are known, but they're cranky and exotic, like a lot of phosphorus chemistry. Actually, a lot of phosphorus chemists are kind of that way, too, in my experience. Like a lot of phosphorus compounds, those aryls probably reek to the skies, too. As for phosphorus chemists reeking, I'd say my personal data set runs about fifty-fifty.

And finally, I'd also like some big, lumpy polar atoms. As it is, if you want to put a single lunker of an atom onto a molecule, you're looking at a bromine substitution. Iodine's possible and even larger, but those compounds are usually too unstable to sunlight to make good drugs, unless you're doing thyroid receptor ligands, where you might have to have them whether you feel like it or not. It's true that a trifluoromethyl group is kind of like a big halogen atom, too. But all these halogens make your molecule rather greasy, which is something we'd rather avoid. Something the size of a bromine that could hydrogen-bond and help its molecule go into aqueous solution would be a big hit. Quantum mechanics, being perverse, has not obliged.

Comments (5) + TrackBacks (0) | Category: Odd Elements in Drugs

May 2, 2004

Odd Elements in Drugs: Silicon

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Posted by Derek

Another chemical element that you don't see much in pharmaceuticals is silicon. Hey, it's right under carbon in the periodic table, and forms four tetrahedral bonds just like carbon does, so why not, eh?

Now, if you're like me, you grew up reading old science fiction stories that posited silicon-based life forms. That seemed pretty plausible to me when I was a kid, and rather a long shot as I got older, but learning chemistry for real made me realize just how unlikely that is. For one thing, silicon-silicon bonds get progressively weaker as you try to make longer and longer chains, as opposed to carbon chains, where there's no real effect. Silicon's more unstable to oxidation than carbon is, too. If you open up a tank of methane, it'll just hiss all over the room. But if you open up a tank of silane, you'd better have the fire department on the line already.

And silicon doesn't form double bonds very well at all, not with itself or carbon (which means, practically speaking, no alkenes and no aromatic rings) or even with oxygen (which means no analogs of amides, for one big thing.) It gives you a new appreciation for carbon, it does.

Your nose can tell that there's something off about the element. It isn't fooled by its position in the periodic table. Many organosilanes have a distinctive, hard-to-describe smell, a sort of flat, spicy, camphor-like reek, and this smell persists over a fairly wide range of structures that normally would be enough to mask it.

But sulfur smells like Satan's socks, and it's vital. There's no problem with working some single-bonded silicon into your molecules, at least on paper. Reasonable organosilanes are stable to normal sorts of things, and there's no particulary toxicity associated with the element. When I was doing my post-doc in Germany, I even saw ads for silicon-containing supplements, which claimed that it was vital for health. That's pushing it, to say the least, but at least it's not vital for sickness.

There sure aren't many examples, though. I'm virtually certain that no human drug has ever been marketed with a silicon atom in it. DuPont actually took a fungicide to market with one, but pharmaceutical chemists look a bit askance at what the crop science folks can get away with. (Where's the challenge, we keep thinking a bit unfairly, in dosing something that doesn't have a gut or a liver?)

There was a cholinesterase inhibitor in development a few years ago with a silicon, and recently there have been some reports of organosilane-based protease inhibitors. A few other such one-offs show up in the literature. From the scattered reports, you can tell that folks have every so often worked up the nerve to take one into the clinic, but nothing's made it all the way through. That keeps many teams from making a big effort, frankly. Who wants to be the first to find out that there's a problem with, say, liver enzymes after ten years of dosing? Most companies would rather let someone else turn over that card.

I've made a silicon analog or two myself over the years, and reaction from my colleagues and supervisors has been, well, mixed. Some fans of the weird cheered the compounds on when they saw them, while other people rolled their eyes almost audibly. None of the compounds were active enough to force any issues, though.

But one small English company is trying to break the silaceous ice, targeting silicon compounds for pharmaceutical use specifically because they believe they've been underexplored. Good look to Amedis of Cambridge, I say. Perhaps they can make the element respectable.

Comments (3) + TrackBacks (0) | Category: Drug Development | Odd Elements in Drugs

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