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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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May 31, 2004

How Not to Do It: Sodium

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Posted by Derek

We have a lot of pyrophoric substances in an organic chemistry lab - things that burst into flame when they encounter normal air. Liquids are handled by syringe and needle, using bottles fitted with gas-tight septae. That works pretty well, once you get the hang of it. The main things you have to learn are to provide some inert gas as a replacement if you're removing a large volume, and to not twitch your arm and hand muscles while you're holding a syringe full of stuff. (That can provide a spectacular flamethrower effect, which is fine if that's what you're after, but we rarely are.)

Pyrophoric solids are a bit trickier. Some of them (like sodium hydride) are often sold as a fine powder mixed with mineral oil, which coats everything and keeps it from igniting. Of course, you have to get rid of it at some point, because it's sure not going to go anywhere. You can either wash off the mineral oil before you begin, while the solid is inside your reaction flask, or clean it away from your compound at the end of the reaction. I usually opt for the latter, on practical grounds: by the time, I'll know if the reaction worked, and I won't have wasted the initial effort on a loser. Besides, most of those reactions need purification anyway.

You can buy dry sodium hydride, but I'm not a fan of the stuff. It goes bad too quickly, and an NaH fire is a beast to put out if it really gets going. A carbon dioxide extinguisher usually isn't up to the job, and it'll blow the powder all over your lab, which isn't recommended. And you most surely don't want to throw water on the stuff, although you'd have to be the village idiot to try that one. You'd certainly get a village idiot's reward for your efforts. The only reliable way to put one of these things out is to bury it in sand or some other inert powder. Then you have to let it cool down for a while - if you don't, it'll just whoomph up on you again when you try to clean the place up. If that doesn't make you feel like you're wasting your day, I don't know what will.

The related potassium hydride is invariably sold in a hard-to-handle suspension that's mostly oil. I've never seen it packaged dry, and I don't want to. It ignites much more easily than the sodium compound, to the point that people even manage to start fires with the oil-soaked item. At least the flames are prettier.

And the metals themselves are usually sold and stored under oil. Sodium metal, as my fellow chemists know, is interesting stuff. It's soft enough to cut with a metal spatula (the texture is rather like cold butter), and is very shiny indeed until the air hits it. You can work with it out like that, if you move with reasonable speed and get it under some inert solvent. Potassium metal is much less forgiving, and I have no desire to work with the heavier metals in the series (rubidium, cesium) as their elemental metals, because they just get worse as they go up.

You can mess up the area with just plain sodium, though, oh yeah. Some collagues of mine had a summer undergraduate (here's where experienced chemists start to grin and pull their chairs closer), and they were teaching him how to handle sodium metal: take it out of the oil, have your beaker of hexane ready, cut it like so, pick it up (the point of the spatula works well), drop it in the solvent, and so on. Everything went fine. So the next day, one of the guys tells him to go down and weigh out, say, five grams of sodium for a reaction. The summer student scampers off, and a few minutes later, the grad student wanders down to have a look, just to make sure things are going OK.

And there the guy is, with his beaker of hexane, sawing away with a spatula at a big cylinder of sodium metal which he is gripping in his bare left hand. Well, he hadn't been told not to do that, true, but neither had he been warned not to fetch it in his teeth. You just sort of take these things for granted. The summer student had no doubt taken the skin of his left hand for granted, too. (It took a few weeks, but he recovered.)

Comments (4) + TrackBacks (0) | Category: How Not to Do It

May 26, 2004

The Latest From the Fishing Hole

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Posted by Derek

Here's an update on my "Catfishing" post from a couple of days ago. I set up around thirty small reactions, with a different potential catalyst in each, looking for something to happen. They sat at room temperature over the weekend, looking very picturesque - with all the transition metals, I had various shades of yellow, red, orange, blue and green scattered around the array.

This excursion has added to my life list of elements used, that's for sure. I'm not sure if I ever would have a chance to use some of these things if it weren't for expeditions like this. Unfortunately, the exotica that I mentioned in the first post has failed to do very much. The vials with things like zirconium, ytterbium or praseodymium salts are just sitting there, as are the fancy iridiums. The coppers have copped out, and a range of rhodiums and rheniums are laughing at me.

The only vials that are showing real changes are the ones with palladium catalysts. That's not too surprising, because Pd is a real workhorse in the catalyst world, for good reason. But I don't think that they're doing what I want. Rather, they seem to be tearing up one of my starting materials and rearranging it into interestingly useless structures, which then find their own list of things to decompose into.

I have another collection of catalysts to try, though, and I'll run those before declaring defeat. I'm going to send a bunch of nickel, iron, and cobalt compounds in to see if they can accomplish anything. If nothing else, they're sure to be decorative. On the other hand, the palladium reactions all look like hot chocolate, which is rarely a good sign.

The first time I tried doing an experiment like this was back in graduate school - I remember going through the labs looking for every Lewis acid that we had in the place. (To a good extent, those reagents parallel Tolstoy's quote from Anna Karenina, in that protic acids are all alike, but every Lewis acid is an acid in its own way). I set those up in vials, too, in a rather more low-tech manner, as befits early-1980s equipment. And here it is, twenty years later, and I'm doing the same thing. It's still fun.

Comments (2) + TrackBacks (0) | Category: Life in the Drug Labs

May 25, 2004

Down the Hatch

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Posted by Derek

We have a lot of received wisdom in the drug business, rules of thumb and things that everybody knows. One of the things that we all know is that the gut wall isn't much fun for our drugs to get across sometimes. That's inconvenient, since most people would prefer to swallow their medicine rather than take part in the more strenuous dosage forms.

Go around asking random medicinal chemists about oral absorption of drugs, and you'll get more things that everyone knows. There will be lots of talk about solubility and allied topics like particle size, salt forms, formulations and so on. Some of this is valid (I'd vote for particle size), but some of it is hooey. For example, I'm not convinced that solubility has much to do with oral dosing (once you get past the powdered-glass stage, naturally.) I've had wonderfully soluble drug candidates that went nowhere, and I've had brick dust that showed reasonable blood levels. I'm just barely willing to admit that there's a trend (in a really wide data set), but I'm not willing to admit that it's a very useful trend. But solubility can be measured (over and over!), so there's a constituency for it.

You'll also get a lot of stuff about P-glycoprotein, and the necessity of doing some sort of cellular assay to see if your compound is affected by it. That's a protein I've spoken about from time to time, which sits in the cell membrane and pumps a variety of compounds from one side to the other. Now, Pgp is a real thing, both in the gut and in the brain. But there are a lot more transporter proteins out there than most of us realize, hundreds and hundreds of the damn things, and we don't have much of a handle on them. I think that they're a big opportunity for drug development in the coming years, assuming we start to get a clue.

People get excited about Pgp because it was one of the first ones characterized, and because it does seem to explain the failure of a few drugs. There's a cellular assay, using the famous Caco-2 colon cells that express the protein, which is supposed to give you some idea of Pgp's effect on the membrane permeability of cour compounds. Unfortunately, I'm not convinced that it gives you much more than a reading of how they behave in the Caco-2 assay, which probably isn't worth knowing for its own sake, to put it kindly. But folks are so desperate to know why their drugs don't get absorbed well (and how they can avoid wasting any more of their working lives on such) that they'll seize on any technique that offers hope.

You'll also hear about metabolism of drug by enzymes in the gut wall, but as far as I can see, that's an overrated fear. (There was a review article on this a few years back from a group at Merck, and that's what they concluded.) People like this explanation because it makes some sense. We all know about liver enzymes ripping our compounds to bits, and here they are in the gut wall! No wonder our compounds stink! And this is also something you can screen for, so you're not left sitting there alone with the black box. Far better to be able to tell everyone that you think you have a handle on the problem and that you're running assays to get around it, even if it isn't true.

Nope, our understanding of drug absorption still reeks of voodoo vapors, despite many attempts at exorcism. It's annoying and it's disturbing, but it's the state of the art. Anyone that can do better will make a fortune.

Comments (10) + TrackBacks (0) | Category: Drug Development | Pharmacokinetics

May 24, 2004

What Ails Us

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Posted by Derek

Before getting started, I'd like to recommend the discussion going on in the Comments section of the "All the Myriad Ways" post below. If you find the topic of gene patents at all interesting, it's worth keeping up with. Me, I'm just watching for now, feeling like Teresa Nielsen Hayden as the discussion takes off on its own. (I show up in her comments section every so often myself, although I largely stay out of the political discussions because I think they'd throw things at me.)

On to the main topic tonight. There's an article in the latest Nature Reviews: Drug Discovery called "Prospects for Productivity" from Bruce Booth and Rodney Zimmel at McKinsey Consulting. They're talking about the now-familiar drug drought that seems to have affected everyone the last few years. It's real enough, although they make the point (which I've brought up myself, in a column for Contract Pharmamagazine) that people have been complaining about a drug shortage for decades.

Booth and Zimmel do a good job of running down the usual suspects. In their order, they have:

1. Lack of payoff from genomics. This one, they say, has "clearly driven part of the productivity decline." I can second that, because I (and friends of mine around the industry) have seen it at work right in front of them. There was a panic that made everyone start working on genome-derived targets, long before we knew enough to accomplish anything. In most cases, we still don't.

2. Poor chemical libraries. This is an earlier problem, but one whose effects are still working their way through the portfolio. The combinatorial chemistry craze (the craze before genomics, if you're keeping score at home) caused a lot of people to make a lot of compounds that had no chance of ever becoming drugs. Why? Because they could make them! And someone else might make them first! We're smarter now, theoretically. B & Z don't go into the details, but this one hit some companies harder than others, depending on how early and how hard they fell for combichem evangelism. Some careers never really recovered.

3. Tougher regulation. B & Z discount this, for the most part, as whining from the drug companies (not their exact wording!) They're probably right, although they correctly note that seemingly minor changes at the FDA have ended up costing huge amounts of money and time on our end. But this still isn't the major thing hurting us, not that it isn't still fun to complain about.

4. Tougher internal scrutiny. This is a real one, too, although it's hard to quantify. We've gotten more cautious over the years, as we've tried to keep from taking drugs deep into clinical trials before finding out that they have some ruinous problem. The early-stage filters and hurdles we've put in probably work a little too well, though. Unnervingly, there are any number of drugs on the market now that never would have made it through the current regimes. The verdict all depends on how many loser projects we're avoiding at the same time, a number that's pretty much unknowable. Ah, what an industry.

5. Unfulfilled technological hopes. This overlaps with some of their other categories (such as all that genomics money we're never going to see again). But Booth and Zimmel draw special attention to the problem of the industry spending huge amounts on better and better in vitro technology (as in the previous point), only to find that it still doesn't translate well to animal models, much less clinical practice. Presumably, we're eventually going to figure out what we're doing, but we're probably going to hose away still more cash while we're doing it, too.

6. Too big to innovate? Readers will recognize this as a particular favorite of mine, what with my happy attitude toward huge mergers. Proponents of such would do well do digest this quote: "Whether size itself is good or bad for R&D remains to be seen, (Heresy! Says the board at Pfizer! - DBL) but the simple fact is that a greater proportion of innovation is occurring outside the industry leaders." Their estimates show a meaningful decline just over the past seven years or so, which is rather alarming for the big guys.

Not a bad roundup. The article has a lot of other useful stuff in it, too; I highly recommend it. They have a few ideas for getting out of our current fix, which I'll try to get to in a future post. None of them strike me as particularly resonant rallying calls ("Improve investment discipline"), but that doesn't mean that they're wrong, either.

Comments (0) + TrackBacks (0) | Category: Drug Assays | Drug Development | Drug Industry History

May 23, 2004

Catalyst Catfishing

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Posted by Derek

I've just spent some time shoveling out piles of spam in the comments of my posts, so this will be a short one tonight. Tomorrow I'll head into the lab and take a look at an unusual setup, something I haven't done in quite a while.

I have about thirty small (20 mg) reactions going, all with the same starting materials. They differ only in the metal catalyst I've added, and I went for the most wide-ranging bunch I could find. I have elements in there that I've never even contemplated using before - stuff like indium, tantalum, ytterbium, and praseodymium. It's quite a sight.

Clearly, I have no idea of what I'm doing. Actually, I know the reaction that I'm trying to accelerate, and I have a rough idea of how it might happen. But beyond that, I don't know enough to guess what might work, so I'm just trying everything that looked reasonable (and a few that didn't, frankly, like the tantalum.) You can come across some interesting things this way, but, truth be told, you usually have to run a lot more than thirty variations to find it.

But it's a start, and I'm looking forward to seeing if anything has happened. I feel like a fisherman going off to check his trot lines. What's it going to be? Empty hooks? Tasty fish? Ugly snapping turtle? I'll report back in the next post.

Comments (1) + TrackBacks (0) | Category: Life in the Drug Labs

May 20, 2004

A Capacious Rat-Hole Indeed

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Posted by Derek

Today's Wall Street Journal kicks off, right in the pole position above the fold, with an article about the total profit/loss figure for publically traded biotech firms, 1990-date. Care to hazard a guess? I surveyed lab colleagues today, and most guesses were something like "Hmm. . .must be a loss, I reckon." One optimist thought they might have been even, or running to a slight profit ("Mostly because of Amgen," he explained.)

Well, the figure is indeed a loss, a 40 billion dollar loss so far. And keep in mind, that's not counting all the venture capital money that's evaporated when companies vanished even before floating stock. An impressive figure!

The natural question is why investors continue to throw money at the sector, and the answer is, as the Journal puts it, "boundless optimism." Reminds me of the chapter title in the stockbroker's classic "Where Are the Customer's Yachts?", titled "Customers: That Hardy Breed." People remember the Amgens of the world, few and far between though they are. As the article points out, a dollar put into Amgen when it went public is worth $165 today. (For comparison, a biotech index fund would have returned 8-fold over that period, and the Dow about 20-fold.)

But there have been a lot more than 165 biotech companies to invest in during that time, so (on the face of it) that 165-to-one payoff is something of a sucker's bet. Of course, we're not just throwing money down on a huge roulette wheel. Biotech stocks are subject to analysis, to a cold-eyed appraisal of their technology and their finances, their burn rates and scientific boards, their patent portfolios and licensing deals and FDA filings. Right? I invest in them too, you know. We're not just buying lottery tickets. We're investing. Right? Anybody?

Comments (3) + TrackBacks (0) | Category: Business and Markets

May 19, 2004

All the Myriad Ways

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Posted by Derek

Closely related to the patenting of biochemical pathways is the patenting of genes. I'm not completely thrilled with that, either, but it still makes a bit more sense to me. With these patents, you own the gene and uses for it, but you don't get to claim everything else downstream of it (like the protein it codes for!) In the first genomic gold rush, the USPTO was swamped with gene applications, and granted quite a few of them without too much in the way of defined utility. Since then, they've tightened up, and you're really supposed to spell out what a gene is good for in order to patent it. Generally, that means using the gene as the basis for a diagnostic test.

In that vein, Myriad Genetics holds lucrative patents on the BRCA1 and BRCA2 breast-cancer susceptibility genes (background here), on which it makes plenty of diagnostic revenue. But it's been losing protection in Europe. Earlier this year, they lost their European patent for BRCA2, and now their BRCA1 patent is history, too.

In general, it's harder to get and hold on to such patents with the European Patent Office, but these decisions seem to have been taken on good old prior-art grounds rather than any finer points. It turns out that a British cancer charity research foundation had applied for BRCA2 before Myriad, which would seem to indicate that the latter's patent never should have even been granted. As for BRCA1, New Scientist reports that the Myriad amended their claims for it in 1995, correcting a few base pairs months after their first filing, during which time the sequence was published in the open literature. Whoops! Can't get a patent after that happens.

Myriad seems to have pretty much given up on the European market for these patents some time ago, what with all the legal trouble. But you have to assume that they're going to continue to pump the US market for all it's worth. Meanwhile, Canada (well, Ontario at least) is just ignoring these patents, according to the New York Times.

A question now is whether Myriad's claims are going to hold up over here. If this were a high-level question about the patentability of genes, the arguing could go on for a long time. But if we're just talking prior art, then it just comes down to some relatively simple issues: are their filing dates just as hosed up here, or not? And even if they are, is there anyone motivated enough to challenge them?

Comments (14) + TrackBacks (0) | Category: Cancer | Patents and IP

The Dose Makes the Poison

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Posted by Derek

If you want to fake it and pass yourself off as a drug discovery scientist - which will cause the velvet ropes to just disintegrate at all the exclusive clubs - then one phrase you can drop is "TI". As in "We need to get the TI up for that", or "What's their TI?" It stands for "Therapeutic Index".

That's just the ratio between the toxic dose of a substance and the medically effective dose. Of course, those can be rather contentious terms, and some arguing goes on during drug development about where to draw the lines. But usually both of them are determined through testing a broad range of doses, and finding out what the dose is to get your desired response in 50% of the animals tested (the ED50) and, at the high end, doses that show the the corresponding onset of tox symptoms and your TD50. A ratio of the TD50 to the ED50 is the classic therapeutic index. More technical details (PDF) are here.

Things get hairy when the efficacy and toxicity start varying between animal models. Sometimes there's more than one kind of toxicity, with different effects that show up in different species, or sometimes it's just because one type of animal is just more sensitive. (Dogs, for example, are famously sensitive to cardiovascular side effects.) If one species shows a nasty TI, you'd better be able to explain it, and explain why you think it isn't relevant to human trials, or your development group isn't going to pick up the phone.

So what's a good TI? Depends on the disease. A value of 2 is cutting things very close, and you're probably going to only get that through when treating something bad. Better to have a minimum of 5 or 10 if you can get it, and the higher the better. No one will give you much trouble with a TI on up in the double digits, unless your toxic effect, when it finally shows up, is something especially heinous.

As you'd guess, the oncology field is famous for narrow TIs, thus all the careful clinical titrating of chemotherapies. Some other classic drugs with rather narrow windows are lithium carbonate for depression and coumadin (warfarin) for blood pressure. Interestingly, aspirin has a narrow TI for an over-the-counter medicine, what with all the gastric and platelet-inhibition effects. While it's a great drug, I really doubt that it would have been developed under current conditions, at least not as we use it now. Is that good (we're safer now!) or bad (how many good drugs are we missing!)

Comments (3) + TrackBacks (0) | Category: Toxicology

May 17, 2004

Next on the Food Channel. . .

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Posted by Derek

I don't know if everyone has been following the comments that are starting to accumulate around here after my posts, but there are some interesting ones. In response to "By Any Other Name", below, I had a report that "a well-known organic chemistry professor" continues to taste various small molecules from his lab.

The person leaving the comment was clearly referring to Nobel-winning professor Barry Sharpless, a famous and very imaginative chemist indeed. I have some points of contact with people from his lab, so I investigated. And by gosh, it's true: Sharpless apparently does taste many newly synthesized compounds, a habit that's been remarked on before: "I taste many chemicals that I make today still. That's not normal. But I'll smell almost everything, even if it's dangerous.''

In sampling compounds, Sharpless seems to observe a rule that (as one witness told me) "anything without a nitrogen in it is probably safe." Before anyone writes to point it out, it's true that mustard gas doesn't have a nitrogen in it, but we can assume that Sharpless is sharp enough to avoid such reactive compounds!

It's not a bad distinction, overall. It's not good enough to make me extend my own tongue, but if you were forced to taste compounds based on one simple rule, you could do a lot worse. You avoid sampling all the alkaloids that way, which is sound advice. Almost all compounds active in the central nervous system have a nitrogen in them somewhere, too, and that's another class of unknowns I'd step aside for.

But the no-nitrogen rule isn't foolproof. There are some mighty foul terpenoids out there, put together with nothing but good old carbon, hydrogen, and oxygen. I'd offer up the carcinogenic phorbol esters as an example. Just looking at the structures, you wouldn't guess that they're as bad as they are. There are plenty of marine natural products that will degrade you, too: the brevetoxins and aplysiatoxins are a real sensation on the tongue, no doubt. And fungi can take you out without nitrogens, no problem at all, as witness the aflatoxins and the hideous trichothecenes.

Granted, Prof. Sharpless probably doesn't take in much of a compound when he gives it his taste test. But I still think I'll leave him to it; he can tell us if he comes across anything interesting. De gustibus non disputandum est. I certainly hope he doesn't poison himself, not least because I find his current work quite interesting. . .

Comments (2) + TrackBacks (0) | Category: Life in the Drug Labs | Toxicology

May 16, 2004

Owning the Road

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Posted by Derek

I mentioned method-of-treatment patents last week, and it's time for me to come back to the topic. These aren't what people think of as "use patents" - the sort of thing you'd apply for when you discover a new use for a known compound. No, method-of-treatment patents seek to own an entire biochemical pathway, and to collect a fee from every drug that might use it.

A fine example of the breed is attempt by a small biotech, Ariad, to exert rights to the NF-kappa-B signaling pathway. (I wrote about this on my old Lagniappe site more than once, and the legal maneuverings are still far from complete.) Ariad is the sole licensee to a patent obtained by the discoverers of this protein, a patent that enumerates, in horrible detail, its two hundred and threeclaims to everything having to do in any way with anything that so much as touches NF-kappa-B and any of its myriad signaling pathways. You have to see it to believe it. The claims are a relentless paving machine, spreading hot asphalt on everything in sight and spraying lane markers for the toll booths. Here's a PDF of Ariad's side of the story, if you'd like it.

Ariad's fired legal shots at several dozen companies, but their lawsuit with Eli Lilly will be the real test. Lilly's sepsis drug, Xigris, works through NF-kB, as does damn near everything else that has to do with inflammation. And their osteoporosis drug, Evista, works through it too, as does damn near everything else that involves signaling through the estrogen receptor. Bristol-Meyers Squibb has already rolled over and paid Ariad, which I have to say seems rather spineless of them, but most other companies have either stalled or told Ariad to take a hike. Needless to say, everyone will be watching the Lilly case with great interest.

I don't know if the case will be fundamental enough to answer the real question, though: should such patents even exist? Not every patent office will grant this sort of thing, although the US PTO sure will. I know what I think: there just seems to be something wrong about being able to set up a turnstile and coin box on a fundamental biochemical pathway.

Now, I know that people patent enzymes, and I know that companies have all sorts of proprietary cells and enzyme systems that they sell. Hey, look at PCR. But what gets me about patents like Ariad's is that they seem to cast too large a shadow. We own the pathway, because we found it first. Does your drug touch it? Too bad - pay up. Didn't know that it did? Not our problem. Not its primary mode of action? Not our problem. You say that you did all the work on your drug yourself and you don't see why you should pay us? Time to read those two hundred and three claims more closely, bub.

The parallels between this and the University of Rochester's fight over COX-2 inhibitors are interesting. Rochester lost the latest round, because the court held that their claim to inhibitors of COX-2 wasn't valid. They hadn't made one, and had no idea of how to make one, but they claimed any inhibitor from anywhere because it touched the magic enzyme. No dice. Will this reasoning gut Ariad's claims?

As you can probably tell, I damn well hope so. I know that there are other companies playing the same game, but I wish none of us were. We're going to cut our own throats by trying to cut everybody else's, if we're not careful. I'm a big fan of patent protection, but I have my limits. I'd like robust protection, sure, but for real objects that do real things. (And yes, this means that I hold business-method patents in contempt, too.) However, I know from my last time writing on this subject that not everyone agrees with me on this, so I'm bracing for a round of comments and e-mail. Good luck convincing me, though.

Comments (6) + TrackBacks (0) | Category: Patents and IP

May 14, 2004

The Last Word on Taste

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Posted by Derek

No time for real blogging for today, but I couldn't let this one go by: Reader Steve C. passes on what has to be one of the worst examples from the old days of tasting new compounds. Back in 1886, Victor Meyer was the first to achieve a reasonable synthesis of bis(2-chloroethyl)sulfide. So, as people did back then, he put some of the damned stuff on his tongue.

A good part of my readership has already grimaced in pain, but the rest of you are about to join them. That compound is better known as mustard gas. Meyer's gourmet experience must have resulted in an excruciating round of terrible blisters - which, depending on the amount he sampled, could have gone on for quite some time. I wonder how many things he taste-tested after that episode?

A blog housekeeping note - my blogroll was shattered in the conversion to Movable Type. It had a number of inactive sites on it, anyway, and there are plenty more I should have added as well. A rebuild is in the works.

Next week we'll talk about method of treatment patents (and won't that be fun, eh?) and about an outfit with the unusual name of Essential Inventions, Inc. The phrase "March-In Rights" will feature prominently, which I hope is not a phrase I'll be using very often.

Comments (2) + TrackBacks (0) | Category: Blog Housekeeping | Drug Industry History | Life in the Drug Labs

May 12, 2004

Beyond the Teeth, Beyond the Pale

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Posted by Derek

The sense of smell is one thing - cast out from its central place in chemistry, it's still an everyday presence. If you want a sense that's really fallen from the sky of the science, try taste.

I'm not old enough to remember the days when people routinely tasted their compounds, but such days there certainly were. If you go back to the early days of organic chemistry (which means, in almost every case, reading German), you find legends like Emil Fischer reporting the appearance, melting point, and taste of all his new carbohydrate derivatives: "Zart", "Suess-Saeure", "Halb-bitter". It gives you the shivers just reading it.

Fine, that was the 1890s. People didn't understand toxicology then, and Fischer didn't know that the phenylhydrazine derivatives he was surrounded by were relentlessly poisoning him. It took a while for people to catch on. Another chiller is the paper (from around 1930) by Alfred Stock where he describes, with detailed examples from his personal experience, the symptoms of chronic mercury poisoning.

But older colleagues of mine fifteen years ago described having tasted the occasional drug candidate earlier in their careers, in very small amounts, just to see if it was bitter enough to be a problem for oral dosing. My guess is that the practice died out in the 1970s, at the latest, but in any case we're talking about compounds that have already been through some rodent toxicity screens, not hydrazones or mercury compounds. The practice of tasting new and unknown organic compounds must belong to the 1940s or before.

Or so I thought. I recently heard a first-hand report from an off-the-beaten track region of Europe that people were tasting compounds there even in the 1980s. I was aghast - the next thing I expected to hear was that the doctors prescribed bleeding for influenza. Who knows what still goes in the backwaters?

Comments (7) + TrackBacks (0) | Category: Life in the Drug Labs

May 11, 2004

By Any Other Name

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Posted by Derek

I mentioned the smell of organosilane compounds the other day, which makes me think of the ambiguous place that smells have in modern organic chemistry. In theory, we're not supposed to smell anything in the lab, or even to be able to. Air-handling systems are supposed to whisk all that stuff away, and besides, we're supposed to be doing all that work inside the fume hood, anyway. Sniffing a compound to find out what it is? A thing of the past - in theory.

But the nose is just too useful. If I have two flasks full of clear liquid, there's no faster way to find out which one has ethyl acetate in it (as long as I'm sure that neither one of them has, say, acetic acid instead.) But it's true that the labs do smell much better than they did years ago. How many years depends on what sort of lab you're talking about. Industrial labs have long been safer places to work than academic ones, and they've long been less smelly, too. I've been in university labs that would knock you down even when no one was working in them, just from the stuff that had permeated the room, and which the air flow clearly couldn't keep up with.

When I was a teaching assistant in the early 1980s, I supervised a standard organic lab where the sophomores made phenyl Grignard reagent. They did it in ether, out on the flippin' bench, because there wasn't enough hood space for everyone to work in. And man, was the ether thick. It has a rollicking vapor pressure under any circumstances, of course, and as the Grignard reactions warmed up you could almost see the mirage-like shimmers in the air as waves of vapor went rolling around.

I taught three lab sections a week that semester, which was the last time I ever TA'ed. The first day was unpleasant, what with all that missing oxygen, for which ether is a poor replacement. The next section was worse, definitely worse. I'd never really minded the smell of ether, but I was finding it a little too much to take. I finished up the afternoon with a terrible headache and a powerful urge for the open air. But come the third lab of the week, I knew that I was in trouble as soon as the first gusts hit me. I had to teach that one from the hallway: "Can you hold that up for me? Higher? Yeah, OK, that looks fine." The only way I could go into the lab without gagging was to hold my breath, exhaling slightly the whole time to avoid the noxious ether fumes.

There's no way that a drug company lab would put up with those conditions, or allow them to happen unless some sort of emergency was in progress. But we still get whiffs of things all the time, weighing reagents out and transferring things around. It's unavoidable, and in such small amounts, relatively harmless. And like anyone with lab experience, I've had small transient exposures to some rather poisonous stuff (cyanide, for example, which doesn't smell as much like almonds as popular lore has it). You can get away with that, but there are some things that you don't want to smell at any level, stuff compared to which hydrogen cyanide fumes are as lilac blossoms on the spring breeze.

The fine chemicals in my "Things I Won't Work With" category over there on the right are in this category. To give another example, here's an entry from the Merck Index whose entry I've always enjoyed, from a distance - fluorine monoxide, the fluorine homolog of water. It's at least a hundred times worse than cyanide, to judge from the toxicity data. According to Merck, it's a ". . .colorless gas. Yellowish-brown when liq. Peculiar smell. Attack lungs. More poisonous than fluorine; delayed appearance of symptoms." Raised eyebrows, followed by a thoughtful silence, is the usual chemist's reaction to the news of something that's worse to inhale than fluorine. And I like that notation of "peculiar smell." Very helpful, that, and it makes you wonder who first noticed it. Probably the poor guy's last words.

Fortunately, fluorine monoxide is unstable, unstorable, unhandleable, and unobtainable. And thus unweaponizable. Anyone who tries is welcome to poison themselves in the attempt, and good riddance, too.

Comments (4) + TrackBacks (0) | Category: Life in the Drug Labs

May 10, 2004

Why Own the Car, When You Can Own the Road?

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Posted by Derek

I've written before about method-of-treatment patents, and now the subject makes today's front page of the Wall Street Journal. They've picked a pure example of the breed. Hans-Ulrich Demuth at the University of Halle in Germany filed for a patent in 1996 on the use of inhibitors of dipeptidyl peptidase IV in the treatment of diabetes. The patent was granted in the U.S. in late 2001 (as US6303661, and no, for those outside the field, that's not an odd delay at all, for better or worse.)

Like many peptidases, DPP-IV is a wrecking ball of an enzyme. It breaks down (among other things) an important signaling protein called GLP-1 (that stands for glucagon-like-peptide 1, which shows you how fuzzy a lot of biochemical nomenclature can be.) And GLP-1 is important in maintaining glycemic control - type II diabetic patients could sure use more of it than they have. If you could find a GLP-1 mimic, you'd have a very interesting drug. That's an unlikely hope for a small molecule, though, so other bounce-shot approaches have been tried. GLP-1 itself has been tweaked in attempts to make it more stable, and people have tried various smaller proteins as well.

There are more. People have tried to cause more GLP-1 to be secreted, without tremendous amounts of success, and then there's the DPP-IV inhibitor approach, which would cause it not to be broken down so quickly. Whatever works! Several companies have taken a whack at this route, because the inhibition of protease enzymes, while still nowhere near a sure thing, has a reasonably good track record in drug development. Novartis is the company in the lead, with a compound well into clinical trials.

Demuth, naturally enough, wants a piece of the action. His first patent claim is for: "A method for lowering elevated blood glucose levels in mammals resulting from food intake comprising administering at least one oral administration of a therapeutically effective amount of at least one inhibitor of Dipeptidyl Peptidase IV (DP IV) or of DP IV-like enzyme activity."

Well, that covers the bases, you'd think. But there's a Prof. Jens Holst in the picture as well, from the University of Copenhagen. His group published a paper a few months before Delmuth's patent was filed, in which they showed the effect of a DPP-IV inhibitor in vitro, and suggested it as an adjunct therapy for diabetes. That's a complication, because if anyone spells out your idea in print, you can't get a patent on it later. (This applies to your own statements, too, which is another reason why we in the drug industry only publish on projects that either well along in the clinic or already dead.)

But Delmuth's patent issued, Holst or no Holst, and he cited the prior work in it. That makes breaking his patent harder, because (presumably) the patent examiner took Holst's work into account and decided to allow the claim anyway. Anyone who wants to say that the earlier publication is invalidating prior art is going to have to prove that the examiner blew it - which certainly isn't unheard of, but is still a harder path to take.

Merck and J&J have already either paid Delmuth or indicated that they're going to. BMS isn't saying what they'll do. Novartis, on the other hand, has so far flatly refused to pay anything. A spokesman told the Journal that they're considering doing some sort of deal, though. You can bet that it's going to be based strictly on the numbers: on one side, figure out how much the drug is likely to make, and find out what sort of cut Delmuth wants. Then factor in how likely it is that you'll actually get to the market. On the other side, how much would it cost in time and legal fees to break his patent? Factor in how likely you think you'll be to win, and you've got the whole equation.

Now, I haven't studied this closely, but that's not going to stop me from having an opinion. (When, since the dawn of time, has that every stopped anyone?) Holst's paper looks like a reasonable candidate for prior art to me, frankly. (He seems to think so, too - he and Delmuth have had some testy exchanges in print.) You'd want to look over the prosecution history of Delmuth's patent, to see if there was any back-and-forthing about it during the examination period. It seems clear to me that the higher the expectations Novartis has for their inhibitor, the less likely they'll be to settle.

But all this suggests the next question, coming up for discussion here within the next few days: should such patents even be granted? Highly paid people are prepared to argue either side of the issue! Heck, I'm even prepared to take one side of it myself.

Comments (6) + TrackBacks (0) | Category: Diabetes and Obesity | Patents and IP

May 9, 2004

Meetings and Their Discontents

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Posted by Derek

I haven't been to any scientific conferences so far this year, and I have to admit that I in some ways I haven't felt the lack. There are a few meetings that I enjoy more than others (Gordon conferences and Keystone meetings come to mind), but there are others that I'd have to be paid extra to attend. Some of the really large ones have been out of control for years (Society for Neuroscience? I'm talking about you.)

You can pick up some good information at one of the better meetings, but even then it can be a strain. Scientific presentations can often be mistaken for a work of the devil: here, I have some important and interesting things to tell you. So I'm going to run it past you once, from fifty feet away, in the dark. Sound good? Or more like a technique to deliberately impair communication? Your best shot is a good poster session or a one-on-one talk, and the Gordon or Keystone type meetings I mentioned earlier are the best ones for that kind of contact.

It doesn't help that many scientists are such notorious speakers. I've had very bad times, there in the dark, watching someone who's clearly using his slides as mnenomic devices ("Next slide, please. . oh, yes, that's right, here's where we were trying to synthesize. . .") or someone who reads off every word on every slide, adding not a syllable of information along the way.

My patience for such things was never very well stocked, and I've run completely dry in the last few years. When I'm listening to a poorly delivered talk, or one on a subject that turns out not to interest me at all, I just sit there thinking of the time that's going to waste and what I could be doing.

At least I'm awake, though. I recall one seminar in graduate school where the visiting speaker pretty much put everyone into a vegetative state from about the second slide. The floor was thrown open to questions at the end, but an embarassing silence ensued. The faculty member who introduced the speaker caught on very quickly, and popped in with a question of his own: "Actually, one of your reactions reminds me of something one of my students is trying right now - right, Paul?" Dead air. "Paul? That addition to the acrylate?" Nothing. Elbows begin driving into Paul's ribs, waking him abruptly back in the next-to-the-last row: "Uh. . .what was the uh, question?"

Comments (3) + TrackBacks (0) | Category: The Scientific Literature

May 6, 2004

A Fire, And Its Flames

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Posted by Derek

The Washington Post ran an article the other day on a home-grown ricin lab in Paris. It's disturbing reading, and it just goes to show how easy the stuff is to make. (I discussed ricin most recently here.)

Mind you, we don't know how good Menand Benchellali's ricin was, or what his batch-to-batch quality control was like, and that's because no one really knows how much of the damn stuff he made or where it all went. Here's hoping his lab technique was terrible, because his subsequent survival would then mean that the stuff wasn't very clean. Being careless around high-quality biotoxins does not make for a long-term career.

Some bloggers quote poems on Fridays. This brings a grim one to mind, unfortunately, which Kingsley Amis pointed out must be one of the only completely serious parodies in English. Starting off from Yeats's "Song of Wandering Aengus", which you should probably read first if you're not familiar with it, a 1974 IRA bombing inspired Roger Woddis to compose:

The Hero

I went out to the city streets
Because a fire was in my head
And saw the people passing by
And wished the smallest of them dead,
And twisted by a bitter past,
And poisoned by a cold despair,
I found at last a resting place
And left my hatred ticking there.

When I was fleeing from the night
And sweating in my room again,
I heard the old futilities
Exploding like a cry of pain;
But horror, should it touch the heart,
Would freeze my hand upon the fuse,
And I must shed no tears for those
Who merely have a life to lose.

Though I am sick with murdering
Though killing is my native land,
I will find out where death has gone,
And kiss his lips and take his hand;
And hide among the withered grass,
And pluck, till love and life are done,
The shrivelled apples of the moon,
The cankered apples of the sun.

I hate to leave everyone for the weekend with thoughts like this, but others are spending their waking hours having far worse ones. Reader, are you a scientist yourself? Do you spend your days going wherever your curiosity takes you, reading what you want to and thinking what you want to think? Not to be crude about it, but it's people like Menand Benchellali, or it's us.

Comments (9) + TrackBacks (0) | Category: Chem/Bio Warfare

May 5, 2004

Price Hydraulics

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Posted by Derek

Just enough time to point out a rarity: a clear-headed article in the popular press about drug prices. Business Week has it, and it's worth a look. (Thanks to reader and colleague Joe C.) I'm glad to see the author acknowledge that efforts to control prices in one area often make them squirt upwards somewhere else.

Of course, the biggest example of that in drug prices is The Rest of the World versus the US. Holman Jenkins ran an article in the Wall Street Journal last week titled "Why Not Import Drugs From Fantasyland?", in which he, with gritted teeth, proposed the reimportation reducio ad absurdum: just take all US pharmaceuticals, toss them over the border into Canada, and reimport the lot. Ta-daa! Lower prices for everyone!

Mind you, many people would read that and say "Yeah! That's it! Under our noses, all along, the answer at last!" I just hope that there aren't a majority of this type in the Senate. . .

Comments (2) + TrackBacks (0) | Category: Drug Prices

May 4, 2004

Deferred Gratification Is Better Than None At All

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Posted by Derek

Bad days for Genta and Allos, as the FDA first made their advisory committee minutes public on Friday, then turned down their drug applications yesterday. Both are nominally cancer therapeutics, and both were seen as tests of a supposedly more open attitude at the FDA, but they're very different situations.

Genta is, at first glance, a time warp of a company. They (and some others, like Isis) have been trying for years to get antisense DNA therapeutics to work. It hasn't been a very rewarding area, although most anyone who've been in the field for ten or fifteen years can recall when it was so hot you couldn't stand next to it. Delivering the DNA (or DNA analogs) has been hard, formulating them has been hard, and showing that they do anything has been very hard indeed. That was Genta's big problem this week. And that means that is was also, to a lesser extent, their partner Aventis's problem. I hope Sanofi wasn't counting on this one, but since I don't really understand why Sanofi went after Aventis at all, who can say?

The compound, Genasense, goes after the production of a protein called Bcl-2, about which more information than you want is here. A lack of Bcl-2 would make cells more vulnerable to programmed cell death (apoptosis - pronounced, if you're as much of a pain as I am, as "ay-po-tosis", not "ay-pop-tosis".) A major thing cancer cells manage to do is to bypass the you're-a-mutant-kill-yourself apoptosis signal and keep on growing, so this is a target of great interest.

But Bcl-2 works through interactions with other proteins, so it doesn't have any real small-molecule binding regions. That makes it a tough target for drug therapy (although that hasn't stopped people from trying.) Antisense or siRNA techniques could potentially stop production of the protein in the cell, though, and provide a completely new cancer therapy. Enter Genasense - and exit it, too, because it doesn't work well enough on its own to be a monotherapy, and didn't meet statistical significance as additional chemotherapy in a trial of over 700 patients.

Genta believes that a subset of the treatment group, the ones who received the compound the longest, showed enough of an effect to approve the compound, though, along with other data on things like mean tumor size. The FDA clearly didn't agree, pointing out the drug's significant toxicity, which decision should throw some cold water on the people who were hoping that things were going to be approved more easily now, with less rigorous efficacy data.

Allos got the cold shower too, but for a different sort of compound. Their RSR13 is a radiation sensitizer, working on the principle that much radiation damage in cells is done through oxidative free radicals. Unfortunately, many solid tumors are rather oxygen-deprived, due to poor circulation, so the Allos approach was to increase the rate of oxygen release from hemoglobin in general. Makes me wonder if they're going to start finding this stuff in the blood of bicycle racers.

Allos went after brain metastases in advanced breast cancer, a patient population that needs all the help it can get. Unfortunately, they didn't reach significance, either, but countered that, you guessed it, a subgroup showed a much larger effect. They might have a point, although it's always risky to ex-post-facto your clinical data. We had a discussion about this on this site a while back, and it was pointed out that for a sufficiently large set of sliced-and-diced subgroups, the real surprise would be if one of them didn't show an outlier effect.

Of the two drugs, though, I find the RSR13 story to have (at least as far as I can tell) a better chance of actually coming true after another round of clinical trials. Antisense worries me, at least in its present incarnation, and I'm not sure how many more forms it's going to get a chance to take. Both stocks were hammered on Friday and Monday, and (truth in trading time) I picked up several hundred shares of Allos today at $2.50 for the long term.

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cancer

May 3, 2004

At My Desk, Playing 500-Card Stud

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Posted by Derek

Hmmm. . .here's an article in the "ASAP" section of the J. Med. Chem. web site. And it's on some compounds in the same therapeutic class that we're working in! Hot news! We finally know what those guys are up to. . .hold it. How long has this paper been sitting around, anyway? I still haven't written up that other project from three years ago - are these guys any better? Why does a paper always seem like breaking news when it's in the preprint section, anyway? It's like headlining the latest arrival in a crypt. At least it does if it's in J. Med. Chem.

Well, it does tell us something we didn't know. I think. But what about that poster that was at the fall ACS meeting? Wasn't that from this same series of compounds? How far in advance do you have to submit those posters, anyway?

They must have patent coverage on this stuff if they're going to go around giving posters and writing up papers. It's got to be in one of those that we already know about. .let's check the ol' patent site here. Yep, eight separate patent filings - don't these people have anything better to do? I hate generic claims - "We claim everything with more than three carbons in it from here to Diego Garcia. We claim that other stuff you're thinking about. We claim yo' mama." By the time you get three pages into this stuff, you're up to your earlobes in definitions for "R38c" and "group ZZX".

But this one looks like it might be the thing - hm, if R3 can be hydrogen, yep, when R5 is lower alkyl, yeah, that's the stuff. So when did they file this thing? In. . .in fall of 2002. Great. Means they were working on it in that spring at the latest. Two years ago - who knows what they're up to now? Come back in three years and I can read about it in the journals, I guess.

The only thing that makes me feel good about the whole thing is that they don't have any better idea what we're up to. Maybe next year we'll flip a card over and give them something to think about. . .

Comments (1) + TrackBacks (0) | Category: Life in the Drug Labs

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