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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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November 30, 2004

More on Woodward

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Posted by Derek

Speaking of R. B. Woodward brings up the usual question: who's the Woodward of today? (Or, in its alternate form, how come there isn't one?)

He doesn't exist. And I wouldn't stand on one leg waiting for one to appear, either. It's too late in the game for that. Woodward was the perfect man for the moment - a generation earlier and he wouldn't have had the tools he needed, and a generation later he would have had too many.

It's generally assumed that we synthetic chemists can make anything we want to, given enough time and money. That's not completely true, but it's true enough to hurt. But no one assumed anything like that forty or fifty years ago. If you'd asked someone in 1955 if they could synthesize Vitamin B-12 if they just had enough postdocs and enough grant money, not many people would have had the nerve to say "yes." (And a fair number of the few who did would have been kidding themselves. . .) But that's the kind of problem Woodward lived for.

Many of the bizarre molecules made by the post-Woodward synthetic gods (Corey, Kishi, Nicolau, et al.) weren't even known in his day. Some of them would surely have given him pause if you'd asked him to take them on with 1960s chemistry. But organic synthesis has improved faster than the complexity of its targets, and the gap isn't what it was. Until we make the leap into some new level of difficulty (speculations welcome), it won't be. And Woodwardosaurus rex will remain extinct.

Comments (0) + TrackBacks (0) | Category: Chemical News

November 29, 2004

Archaeologists Announce Dirty Laundry Discovery

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Posted by Derek

Hey, brain researchers! Want to unravel the fine details of long-term memory? Looking for the longest of long-term potentiations? Just go out and rope in a few scientists. No, not to do the research - to do the research on. If you can find some that feel that they've been cut out of the credit for a discovery, you've got the best subjects you could ever want.

Consider some research that look place in the mid-1960s at Harvard. R.B. Woodward was Harvard's star organic chemist, a man whose name is still used as a shorthand for extraordinary talent. His work with Albert Eschenmoser to synthesize Vitamin B12 is considered one of the great syntheses of all time, and it was a set of problems in that project that set him to working with theoretician Roald Hoffmann to codify what was going on. Chemists everywhere are now familiar with the Woodward-Hoffmann rules for pericyclic reactions, which tied a whole list of cyclizations and rearrangements into a coherent bundle. Hoffmann and his collaborator Kenichi Fukui won the 1981 Nobel prize, and if Woodward had been alive he very likely would have joined them to win his (nearly unheard-of) second one.

Enter E. J. Corey, who took over the position of mighty synthetic powerhouse at Harvard after Woodward's death and won a Nobel of his own in 1990. In his acceptance speech earlier this year for the American Chemical Society's Priestly Medal, Corey mentioned the Woodward-Hoffman work, and mentioned in passing that he had actually put Woodward onto the path that led to the correct solution. This was news to just about everyone - well, except for a few people Corey had complained to over the years, not least of them Roald Hoffmann himself.

Now Hoffmann has replied, in a highly unusual five-page letter in Angewandte Chemie. (Those links may not work for nonsubscribers - try this roundup from Nature instead.) He goes into a lot more detail than Corey's spoken claim did, feeling (correctly, I'd say) that the gloves are now off. As it turns out, Corey wrote a letter to Hoffmann in 1981 giving his account of his conversation with Woodward, and describes how the next day he heard Woodward refer to the idea as his:

"In a manner of which few would be capable he pirated the idea, evidently preferring that over my good will. Even more incredible than what Bob did was how he did it. . ."

Thus said Corey, and he attached a plea that Hoffmann set the record straight in his Nobel acceptance speech. This chance Hoffman declined, as anyone would have guessed, since Bob Woodward had been dead for two years and the only person who could attest to the conversation was Corey himself. A follow-up letter from Corey was full of unretractable fighting words. Hoffmann mentions that he went on to meet with Corey personally in 1984, but how he managed to make himself do that after this sort of stuff is beyond me:

"You cannot deny that despite the possibility of appalling dishonesty at the roots of your collaboration with Bob, you elected to close your mind. . .please consider that history many not deal leniently in this matter, taking seriously the possibility not only of Bob's dishonesty, but of your own not unwitting participation in the extension of fraud."

Hoffmann goes into great detail on his side of the 1964 story, and he has some good evidence that Woodward was already on the track of the idea that Corey claims to have suggested to him. (He also reports that Woodward denied to him that Corey was a contributor to the work, but that's another conversation we have only one side of.) But Hoffmann also gets in a kidney punch, showing that Corey published a paper the next year that would have been an ideal showcase for his understanding of the relevant concepts, but said nothing about them.

Corey never went public with his claim until this year, although it seems that for years he's vented to a number of prominent chemists and fellow Harvard faculty members. It's clearly been eating away at him all this time, and for some reason - intimations of mortality? - he feels that it's time to haul out this ancient dispute.

I never met Woodward - first-year undergraduates in Arkansas didn't cross his path much - but I've met (casually) both Corey and Hoffman, and I've worked with students and post-docs of all three of them. Overall, I'd say I believe Hoffmann here. Although I think that Corey probably did have what he saw as a key conversation with Woodward in May of 1964, I'm not so sure that Woodward saw it as such a turning point. There's no way for us to know - even if Woodward had lived to comment, I doubt if that would have cleared things up any more. (Of course, Corey had fifteen years to speak up while Woodward was alive, a point Hoffmann misses no opportunities to make.)

What I'm sure of, though, is that Corey is doing himself no good at all. Chemists all over the world are saying to themselves "This guy has a Nobel already, what else does he want?" One problem is that some of this springs from the same qualities that got Corey to where he is. The persistence that's kept this simmering in him from 1964 to 2004 is the same persistence that's taken him through a huge array of impressively difficult molecules. But this is all a useless wound to his own reputation. There are, after all, more important things than being right.

Comments (4) + TrackBacks (0) | Category: Chemical News

November 28, 2004

Some Perspective

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Posted by Derek

I remember when this year started that I said that no one in the industry was going to miss 2003, but I think that a lot of folks would trade in 2004 to have it back. I'm pretty easygoing, but man, this has been one of the worst stretches for the drug business that anyone can recall. Every week brings more news of layoffs, regulatory troubles, lawsuits and investigations. We have a front-row seat for the long-running show titled One Damn Thing After Another, and the intermission is not yet in sight.

I won't bother to link to all the individual stories - just go to any news site and enter in the name of a drug company. Odds are the first story that comes up will be negative. It's quite a sight.

But it's important to keep some perspective, even as another load of subpoenas and rotten tomatoes comes in over the transom. The drug industry isn't going away. We perform a vital service, and it's just going to get more important with time. We, our current customers, even the same people who are howling for our heads now will need medicines. And (for many years to come) we - for all our faults - will be the only people who even have a hope of delivering them. We just have to hold on, and hope that all this is a period of creative destruction, rather than the standard bulk-rate kind.

Comments (3) + TrackBacks (0) | Category: Drug Industry History

November 23, 2004

Chemistry Geekery

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Posted by Derek

Since I mentioned the other day that I've never done an ozonolysis reactions, I thought I should come clean about some other classic reactions that I've never had the need to perform: I've never run a real aldol reaction, for one. That's partly because I did a lot of carbohydrate-based synthesis early in my career, so I already had all the aldol-like products I needed. Now, I've run a few retro-aldol reactions, but none of them deliberately, I'm sad to report. They just up and happened, and at unfortunate times.

I've never run a diazotization (Sandmeyer) reaction. I've nothing against them (well, except on large scale, maybe), but I've never quite needed one. I've never used selenium for anything. I've never made diazomethane (although I've used someone else's, parasite that I am.) Nor have I ever done a Fischer indole synthesis, a Skraup reaction, or a Nazarov cyclization. They've waited this long; they can wait some more.

I've never done an olefin metathesis reaction, which means that the trend started without me and will leave without me. I've yet to use samarium iodide for anything, although it's been close a few times. The Hell-Vollhardt-Zhelinsky reaction has passed me by, as has the Oppenauer oxidation, the Wacker oxidation, and doubtless several others.

What have I done? Most of the remaining famous ones, as far as I can tell. Sometime I'll unleash a list of the more obscure ones that I've run (Shapiro reaction, anyone?), and we'll have a name-reaction fiesta.

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

I Don't See How This Qualifies As Bliss

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Posted by Derek

No blogging window for today - there will be a post tomorrow, and then I'll take a break until next Monday. For now, I recommend this post over at Uncertain Principles. Its implications for public discussions of drug discovery and safety should be pretty clear (as will the title of this post, for that matter!)

Which reminds me - I've been rebuilding the blogroll over there on the left, and I encourage you to check out any that you're not familiar with. More sites are coming, including a lot of the medical/pharma links that I had before. Suggestions welcome.

Comments (1) + TrackBacks (0) | Category:

November 21, 2004

Safe, And Other Four-Letter Words

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Posted by Derek

According to the FDA's safety maverick, David Graham, there are at least five approved drugs out there that are unsafe and should probably be pulled from the market. Roche's Accutane, AstraZeneca's Crestor, GSK's Serevent, Pfizer's Bextra and Abbott's Meridia are all on his chopping block.

Well, Graham may not feel that he has enough power at the FDA, but he sure swings some weight in the stock market. All these companies lost several per cent of their market value on Friday, taking the whole drug sector with them. What everyone wants to know is: are these drugs safe?

What a useless question. I mean it - we're never going to get anywhere with that line of thinking. "Safe" is a word that means different things to different people at different times, which is something you'd think any adult would be able to understand. The only definition that everyone would recognize, at least in part, is "presenting no risk of any kind to anyone." That'll stand as a good trial-lawyer definition, at any rate.

And by that one, not one single drug sold today is safe. Of course they aren't. These compounds do things to your body - that's why you take them - and that's inherently risky. I don't think that I'm alone in the drug industry as someone who never takes even OTC medication unless I feel that the benefits outweigh the risks, and the risks are never zero. I know too much biochemistry to mess around with mine lightly.

The drug industry, the FDA, physicians and most patients recognize that safety standards vary depending on the severity of the disease. Toxic drug profiles are tolerated in oncology, for example, that would have stopped development of compounds in almost other area. And the standards go up as additional drugs enter a market - yes, I'm talking about those evil profit-spinning me-toos. One of the best ways to differentiate a new drug in a category is through a better safety profile.

So when someone asks, "Is drug X safe?", they're really asking a whole list of questions. What are the risks of taking the compound? That is, how severe are the side effects, and how often do they occur? How do those stack up against the benefits of the drug? Then you ask the same set of questions in each patient population for which you have distinguishable answers.

To pick an example from Graham's list, Accutane has big, dark, unmissable warnings all over it about not taking the drug while pregnant or while it's possible to become pregnant. Has that stopped people? Not enough of them, unfortunately. And this is a drug for acne, which can be disfiguring and disabling, but is not life-threatening. If it were a drug for pancreatic cancer, we wouldn't be having this discussion.

The COX-2 inhibitors look much better (in a risk-reward calculation) in the patients who cannot tolerate other anti-inflammatory drugs because of gastrointestinal problems. Vioxx itself also looks a lot more reasonable in patients who are not in the higher-risk cardiovascular categories. But it (and the others in its class) have been marketed and prescribed to all kinds of people, and the fallout is just starting. How about Pfizer's Bextra? As an article in the New York Times aptly puts it:

"Another disaster in the making? No one knows. The parallels between Vioxx and Bextra are eerie. There are mounting worries about Bextra's safety, just as there were with Vioxx. Drug-safety advocates are calling Bextra a danger, just as they did with Vioxx. Pfizer, Bextra's maker, defends its drug just as Merck did. And studies of Bextra provide ammunition to both sides, just as studies of Vioxx did.

What should the F.D.A. do? The answer is as clear as mud, just as it was with Vioxx. The twin controversies demonstrate the problems that the F.D.A. routinely faces in trying to strike the right balance between the risks and benefits of prescription drugs. There is almost never a perfect answer. . ."

Strike that "almost", guys.

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

November 18, 2004

Nine Things I'm Having Trouble Imagining

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Posted by Derek

1. An issue of Chemical and Engineering News with an article about how we have about the right number of chemists. Not a critical shortage, not a worrying surplus - just what we seem to need, if only by accident.

2. The lowest-priced supplier for a reagent turning out to be Aldrich.

3. A total synthesis paper that doesn't spend the first two paragraphs trying to convince me - and probably themselves - that the molecule was worth making.

4. A chemistry department graduate student lounge that doesn't make you want to throw yourself under the wheels of a bus.

5. An issue of the Journal of the American Chemical Society without some report of nanorods of something, anything, you name it. Complete with photo.

6. An HPLC column salesman who tells me that yes, there is a problem or two that his company's products have not been known to solve.

7. Hanging a solubilizing group off of a lead compound structure and having the new molecule actually work better than the old one. You'd think random chance would have provided me with this experience by now, but you'd be wrong.

8. A protein tyrosine phosphatase inhibitor that actually works. You know, well enough where someone might pay money someday to put it in their mouth.

9. A vital competitor patent, five hundred pages long with nine Japanese inventors. . .written in English. Or German, or French, or Mayan heiroglyphics or anything other than Japanese.

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

November 17, 2004

RNAi: The Awkward Age

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Posted by Derek

A notable feature of 21st century molecular biology (so far!) is the emphasis on RNA. I've written before about RNA interference, a hugely popular (and hugely researched) way to silence the expression of proteins in living cells. Wide swaths of academia and industry are now devoted to figuring out all the details of these pathways, key parts of which are built into the cellular machinery. They turn out to regulate gene expression in ways that weren't even thought of before the late 1990s, and I've said for several years now that this field is the most obvious handful of tickets to Stockholm that I've ever seen. (Naturally, there are some worries that the whole field has perhaps been a bit over-promoted. . .)

Shutting off the production of targeted proteins is a wonderful thing, both from the basic research viewpoint and the clinical one. The more control you can have over the process, the better, and RNAi has been extremely promising. But as we're learning more about the system, complications are creeping in. Don't they always. . .

It turns out that the small interfering RNAs that are used, and are supposed to be the most efficacious and the most specific, aren't always what they seem. A disturbing recent study used one targeting luciferase, a firefly protein with no close relatives in the human genome. But applying it to the human-derived HeLa cell line showed effects on over 1800 genes - some of which only showed up at high concentrations, true, but none of these would have shown up at all in the ideal world we might have been living in for a while. There have also been experiments with RNAs that have deliberately made with slight mismatches for their intended target, and some of them work rather too well.

Finally, as I mentioned about a year ago, there are reports that these small RNAs can set off an interferon response, suggesting that the technique can cause cells to respond as if they're under infectious attack. As you'd imagine, this can also complicate the interpretation of an experiment, especially if you're already targeting something that might interact with any of these pathways (and plenty of things do.)

None of these yellow flags are particularly large, but there are several of them now and probably more waiting to be noticed. (A good brief roundup of the situation can be found in the November issue of Trends in Genetics, for those with access.) Perhaps as we learn more we'll find ways to obviate these problems. If there's one thing for sure, it's that we haven't figured out all the tricks that RNA is capable of. But the companies that are racing to get RNAi therapies into the clinic are watching all this a bit nervously, hoping that they're not going to be those fools that you always hear about rushing in.

Comments (3) + TrackBacks (0) | Category: Biological News

November 16, 2004

Things I Won't Work With: Ozonides

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Posted by Derek

I've never done an ozone reaction myself. In fact, I haven't seen anyone else do an ozonolysis in years now, and I wonder if this reaction is passing into chemical history. These guys are hoping not.) Many chemistry departments have an electric gizmo to produce ozone in small quantities, and I get the impression that they're mostly gathering dust.

Ozone attacks a carbon-carbon double bond, initially making an ozonide, a hair-raising five-membered ring that has three oxygens in a row. That rearranges to a still-alarming one with two on one side, separated by carbons from the other. That falls apart on workup to two carbonyl compounds (or other things, depending on what you add to the reaction.) It's a very clean way to oxidize a double bond and make reactive handles out of its two ends.

But it tends to be something that's done on a small scale, because those ozonides are packed with energy and ready to hit the town. In general, we chemists shy away from compounds with lots of single bonds between the elements on the right-hand side of the periodic table. Those guys tend to have a lot of electron density on them, and bonding between them is a careful, arm's-length affair, sort of like porcupines mating. Two oxygens single-bonded make a peroxide, and those generally blow up. A small ring with more oxygens in it than carbons will almost invariably blow up if you try to concentrate it or handle it too briskly.

I'd do an ozonolysis if I needed to (although first I'd have to find our machine and see if it even works.) But you couldn't pay me to try to isolate the intermediate ozonides. But you can pay some people, like Prof. Pat Dussault, who was a post-doc down the hall from me when I was in graduate school. He's made a career out of oxygen-oxygen bonds, no small feat.

Comments (13) + TrackBacks (0) | Category: Things I Won't Work With

November 15, 2004

Keep It To Yourself

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Posted by Derek

I've mentioned how patentability can be ruined by any sort of prior publication, but - since we're talking about the law, after all - there's always room to argue about what a "publication" might be. That's been clarified a bit by the recent In re Klopfenstein decision, available herein all its legal glory as a Word document.

Carol Klopfenstein and John Brent filed an application in 2000 for a method to lower cholesterol and increase HDL by including soy cotyledon fiber in food. They appear to have had an improved method for producing and using the substance. No problem there - patents are filed all the time for methods like that - but it turned out that their invention had been the subject of a poster presented at the American Association of Cereal Chemists meeting in 1998. The poster had no printed handouts to go along with it, and was displayed for about three days. Unlike many such poster sessions at meetings, it wasn't catalogued or indexed in any publication. Later that year, the same poster was displayed for an afternoon at Kansas State.

And on that basis, the PTO turned down their application, saying that this was a public presentation. Klopfenstein and Brent appealed the examiner's decision, but it was no dice. Said the court:

"The factors relevant to the facts of this case are: the length of time the display was exhibited, the expertise of the target audience, the existence (or lack thereof) of reasonable expectations that the material displayed would not be copied, and the simplicity or ease with which the material displayed could have been copied. . .Upon reviewing the above factors, it becomes clear that the (poster) was sufficiently publicly accessible to count as a "printed publication". . .The reference itself was shown for an extended period of time to members of the public having ordinary skill in the art of the invention behind the '950 patent application. Those members of the public were not precluded from taking notes or even photographs of the reference. And the reference itself was presented in such a way that copying of the information it contained would have been a relatively simple undertaking for those to whom it was exposed-particularly given the amount of time they had to copy the information and the lack of any restrictions. . ."

This doesn't surprise me, because in the drug industry there's no way that we would show a poster on anything before the patent application had been filed. We err on the side of caution. But if you're an inventor and wants to live dangerously, there are still ways to be a disclosure daredevil: for example, if this poster had only been displayed for an afternoon, it might well not have counted. A disclaimer that they didn't want the information on it copied would have done the trick, although I have to say I've never seen one of those in a poster session. And if the key data had been buried inside the presentation in a way that was difficult to comprehend and copy (and man, have I ever seen some posters that fit that description), that might have slipped by, too. But it was out there too long, too openly, and with no reason for anyone not to copy it.

That hasn't stopped some law firms from issuing ominous-sounding releases about how the courts are trampling on the patent rights of individuals. But that's ridiculous. Here's a free clue: if you want to patent something, you should avoid writing it on a big piece of posterboard and showing it off to anyone who walks by.

I do have one question, though, which I haven't seen answered in any of the accounts of this case that I've read: how was the AACR poster brought to the attention of the Patent and Trademark Office if there was no record of it? I'm sure there's a good explanation; I just don't know what it might be.

Comments (4) + TrackBacks (0) | Category: Patents and IP

November 14, 2004

I'll Have the Lot

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Posted by Derek

Thanks to the Patnews mailing list, I was made aware of an alarming patent application from Genentech (WO2004060270, for intellectual property aficianados following along at home.) It's pretty unremarkable, if you just look at the front page. Two inventors, and a bland one-sentence abstract: "The present invention is directed to compositions of matter useful for the diagnosis and treatment of tumor in mammals and to methods of using those compositions of matter for the same."

Generic as can be - that sentence would do, if you were pressed for time, for any of several hundred patent applications that come out every year. Walking around the patent landscape, you'd never stop to pick that one up. But just try it. . .hmmm, seems to be buried in the ground a bit. Dig around, and it's larger than you think. . .you're going to need a shovel to get this thing out. As you go on, this nondescript little pebble turns out to be a bump on the anchor of an entire buried aircraft carrier, and a fleet of diesel-powered backhoes aren't going to be enough to unearth it.

This is just how you feel if you're foolish enough to try to download this thing. My company subscribes to a service called Micropatent, which for a fee gives you access to just about every application and issued patent you could want. Check-mark this one and they cheerfully inform you that it's five thousand and fifty-four pages long. Better make sure that the printer is still under a service contract.

It turns out that this behemoth contains over four thousand gene sequences, presumably the compositions of matter that they're talking about. Now, this would have (almost) made sense eight or ten years ago, in the land-rush era of genomic sequencing. People were flooding patent offices with all kinds of flimsy applications as soon as they got an open reading frame. But a few years ago, the various authorities began to tighten up on this sort of thing.

They wanted to see a lot more enablement of the claims that were coming in - no longer could you say: "I claim gene sequence ATCGAAGTA, etc., and all the diagnostic methods for whatever diseases turn out to be associated with it and any treatments that make someday make use of it and whatever else might end up turning a buck, that too." But that looks like just what Genentech is saying here. The patent has a priority date of October 2002, long after this kind of nonsense was supposed to have packed up.

What's going on? It's no afternoon's work, putting together a five-thousand-page application, and prosecuting it is going to get pretty expensive for a practical joke. I have to presume that they have a reason, but it's hard to see what it might be. The only thing I can think of is that they want to spray down all of these sequences as prior art.

Perhaps Genentech has an idea that there are some useful things in this haystack, but no way to be sure which ones they are. They know, appearances aside, that it's not 1994 any more, and they won't be able to get real patent rights for such a fishing expedition. So if they can't own them, well, here's the way to make sure that no one else can, either. Publish 'em openly, and they're non-patentable. The only problem is that no journal would accept a paper with a title like "Forty-Five Hundred Gene Sequences That Might Be Of Use Someday", with five thousand pages of supplementary material. Heck, they wouldn't have even taken that in 1994.

But the patent office will take it. They'll take most anything if you pay the filing fee, and the application will publish in a year or two no matter how hideous it is. It'll be interesting to watch the prosecution of this one. It's hard to imagine that Genentech is seriously going to take thing thing on and let it nationalize. Nope, my bet is that they're just going to drop it. The mission has already been accomplished.

Comments (4) + TrackBacks (0) | Category: Patents and IP

November 11, 2004

Alexander Would Have Understood

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Posted by Derek

You'd think that by now most reasonably simple chemical structures would have been explored, but it's funny how many untouched areas still exist. I was looking at one the other day, which I certainly can't specify, but it surprised me that such a small "drug-like" template hadn't been worked on. I expected to see a message like "1097 substances, displaying 1-25" displayed in SciFinder - the chemists in the audience will know the kind of search results I mean.

It's things like this that keep us in business, from a patent perspective. But patentable chemical space isn't a renewable resource. There are already large areas where it's basically impossible to get coverage - try for some reasonable indoles, piperazines, or imidazoles, for example. You'll have to get fairly baroque in the side chains before you'll find any uncleared territory.

We use up big chunks of intellectual-property real estate every year. Even when a patent expires, it's prior art forever, and that goes for publications of all kinds. (A recent court case established that even rather obscure and limited poster presentations are public disclosures sufficient to make their contents unpatentable.) When will we run out of frontier? And what will we do then?

Comments (5) + TrackBacks (0) | Category: Patents and IP

November 10, 2004

Cui Bono?

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Posted by Derek

Holman Jenkins has an interesting "Business World" column in today's Wall Street Journal. Writing about Merck and Vioxx, he wonders:

"Did CEO Ray Gilmartin blunder in withdrawing Vioxx from the market? Merck executives yanked the prescription pain reliever, amid much backpatting, when a study revealed that long-term users were at somewhat elevated risk for heart attacks and strokes.

Merck was evidently bidding for public admiration in sacking its biggest revenue spinner. If so, the tactic seems to have failed catastrophically. And contrary to the tone of much recent coverage, doctors had long understood that patients taking Vioxx would suffer more heart attacks than patients taking conventional pain relievers."

I didn't think that Merck was looking for good-conduct points, actually - what changed was that there was finally a large-scale study that showed irrefutable evidence that there was a cardiovascular problem. Jenkins goes into this a bit, but I think that it's clear that if Merck wasn't going to act, then the FDA would have forced them. Perhaps that's the only good PR that they might have been hoping to salvage. He goes on to make a very useful point:

"Merck chose to withdraw the drug, although honesty would have been equally well-served by a big informational campaign saying: "Don't prescribe this for patients not at risk for stomach bleeding. Don't let patients become chronic users."

Given that market surveys show that two-thirds of Cox-2 users don't need them, Merck's revenue hit would have been devastating in either case. But it would have made the point that Vioxx is not a defective product -- all drugs have risks that have to be weighed against their benefits -- but a seriously overprescribed one.

The Vioxx debacle is symptomatic of a system that shields consumers from price signals and sometimes actually discourages them from making the right health-care choices. . .Big Pharma is well along in being corrupted by third-party payership, just like the rest of the health-care industry. Drug makers increasingly aim their development efforts at the aches, pains, insecurities, heartburn and erectile dysfunction of price-insensitive, over-insured baby boomers because that's where the money is.

The problem is compounded by a regulatory system that drives the cost of developing a new drug to a billion or more, then forces companies to recoup all their costs in a few short years before the patent expires. This basically forecloses a great deal of investment in drugs that don't fit the above description, such as vaccines or antibiotics."

Unfortunately, there's an awful lot of truth in that. Since we're a business, we are always going to look for where the most money can be made. Other things being equal, underserved markets would be some of those places. But with the increasing difficulty of finding drugs and getting them to market, the pressure to get your few, rare shots to land right has increased. Thus the situation that Jenkins describes - and this is where I part company with the Marcia Angells and Merrill Goozners of the world.

They see the current situation and say "See! The big drug companies are just going for the big profitable diseases! That's why pharmaceuticals are in the shape they're in!" And from our end, it looks more like "Things are in such bad shape that we'd better stick to the big, profitable diseases. If we spend all our time targeting the others, we'll go under!" It's a cause-and-effect argument.

And the larger point stands as well: I think that companies should, in fact, shoulder blame for promoting Cox-2 inhibitors as if they were the right choice for everyone, and for pushing things like Nexium over Prilosec (and Prilosec over the older drugs in the category, for that matter.) But there's plenty of blame to go around.

Physicians have to write prescriptions for these things for us to sell them. Have the doctors been stampeded by our marketing departments, bribed by our piles of loot, or are they worried that if they don't write for these drugs then the next doctor will? And what about the insurance companies who are paying for all this stuff? To me, those are the people whose actions make the least sense.

Comments (5) + TrackBacks (0) | Category: Drug Prices

November 9, 2004

Gumming Up the Amyloid Works

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Posted by Derek

The October 29th issue of Science has an interesting article from a team at Stanford on a possible approach for Alzheimer's therapy. The dominant Alzheimer's hypothesis, as everyone will probably have heard, is that the aggregation of amyloid protein into plaques in the brain is the driving force of the disease. There's some well-thought-out dissent from that view, but there's a lot of evidence on its side, too.

So you'd figure that keeping the amyloid from clumping up would be a good way to treat Alzheimer's, and in theory you'd be correct. In practice, though, amyloid is extremely prone to aggregation - you could pick a lot of easier protein-protein interactions to try to disrupt, for sure. And protein-protein targets are tough ones to work on in general, because it's so hard to find a reasonable-sized molecule that can disrupt them. It's been done, in a few well-publicized cases, but it's still a long shot. Proteins are just too big, and in most cases so are the surfaces that they're interacting with.

The Stanford team tried a useful bounce-shot approach. Instead of keeping the amyloid strands off each other directly, they found a molecule that will cause another unrelated protein to stick to them. This damps down the tendency of the amyloid to self-aggregate. The way they did this was, by medicinal chemistry standards, simplicity itself. There's a well-known dye, the exotically named Congo Red, that stains amyloid very powerfully - which must mean that it has a strong molecular interaction with the protein. They took the dye structure and attached a spacer group coming off one end of it, and at the other end they put a synthetic ligand which is known to have high affinity for the FK506 binding protein (FKBP). That one is expressed in just about all cell types, and there are a number of small molecules that are known to bind to it.

The hybrid molecule does just what you'd expect: the Congo Red end of it sticks to amyloid, and the other end sticks to FKBP, which brings the two proteins together. And this does indeed seem to inhibit amyloid's powerful tendency for self-aggregation. And what's more the aggregates that do form appear to be less toxic when cells are exposed to them. It's a fine result, although I'd caution the folks involved not to expect things to make this much sense very often. That stich-em-together technique works sometimes, but it's not a sure thing.

So. . .(and you knew that there was going to be a paragraph like this one coming). . .do we have a drug here? The authors suggest that "Analogs based on (this) model may have potential as therapeutics for Alzheimer's disease." I hate to say it, but I'd be very surprised if that were true. All the work in this paper was done in vitro, and it's a big leap into an animal. For one thing, I'm about ready to eat my own socks if this hybrid compound can cross the blood-brain barrier. Actually, I'm about ready to sit down for a plateful of hosiery if the compound even shows reasonable blood levels after oral dosing.

It's just too huge. Congo Red isn't a particularly small molecule, and by the time you add the linking group and the FKBP ligand end, the hybrid is a real whopper - two or three times the size of a reasonable drug candidate. The dye part of the structure has some very polar sulfonate groups on it, as many dyes do, and they're vital to the amyloid binding. But they're just the sort of thing you want to avoid when you need to get a compound into the brain. No, if this structure came up in a random screen in the drug industry, we'd have to be pretty desperate to use it as a starting point.

Science's commentary on the paper quotes a molecular biologist as saying that this approach shows how ". . .a small drug becomes a large drug that can push away the protein. . ." But that's wrong. You can tell he's from a university, just by that statement. I'm not trying to be offensive about it, but neither Congo Red nor the new hybrid molecule are drugs. Drugs are effective against a disease, and this molecule isn't going to work against Alzheimer's unless it's administered with a drill press. If that's a drug, then I must have single-handedly made a thousand of them. The distance between this thing and a drug is a good illustration of the distance between academia and industry.

To be fair, this general approach could have value against other protein-protein interaction targets. I think that it's worth pursuing. But I'd attack something other than a CNS disease, and I'd pick some other molecule than Congo Red as a starting point.

Comments (3) + TrackBacks (0) | Category: Academia (vs. Industry) | Alzheimer's Disease

November 8, 2004

Merck's State of Mind

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Posted by Derek

It may not be known outside the industry, but what Merck is going through right now must be particularly painful just because it's happening to Merck. Now, as I mentioned the other day, I have a lot of respect for the company and for many of the people who work there. (See "Let's See What the Sharks Think of These Steaks!" on Nov. 2nd, below.) But no one in the business would deny that Merck has always considered itself a bit elevated from the common herd. Sometimes that's been justified, sometimes not. But with that attitude in place, which it has been for decades, the company's troubles must be even harder to confront.

Other companies have had painful near-death experiences, of course, and their corporate cultures reflect it. At a place that's been through a major episode, you can pick up defiant we-survived-that-and-we'll-survive-this-too music, and philosophical all-things-must-pass stuff, too. But the one thing that everyone at such a company knows is that all things can come to pass, that terrible problems can come flapping and screeching down with no warning. They know that they're not immune.

I'm not completely sure that everyone at Merck had internalized that. To be sure, the last couple of years have been pretty rocky over there, with several advanced clinical candidates disappearing amid bonfires of money. But those are jsut the normal breaks of the drug-discovery game, unfortunately, and they probably weren't enough to shake Merckian confidence. After all, if a compound runs into esoteric trouble late in the clinic, how were you to know? That's what research is for!

But Vioxx, now that's a different story. "How were we supposed to know?" is not a rhetorical question any more. Highly motivated lawyers are lining up to try to prove just how Merck was supposed to know. They'll be hammering away at themes of negligence and incompetence, of conspiracy and culpability. I don't know if the effort will succeed, (although those internal memos that have surfaced makes rethink the odds), but the pummeling that Merck is going to get will surely have an effect.

In the end, Merck is likely going to have to emit ten to twenty billion dollars. But that's not the effect that I was talking about. That's just money - well, just an awful lot of money - and they could conceivably earn it back, given the time and luck for a brutal retrenchment. (We'll leave aside for now the question of whether there's enough of either available.) But Merck's good name is in for a trampling, as is Merck's confidence. There are probably plenty of people there who don't realize yet just how thoroughly both of those are being lost.

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

November 7, 2004

Take it Off!

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Posted by Derek

When I was an undergraduate, learning all the chemical reactions that you have to learn in undergraduate courses, I got a few wrong ideas into my head. Well, probably more than a few, but you know what I mean.

One of them came from Theodora Greene's book on protecting group chemistry, which was a new item in its first edition around the time I was doing my first summer research project. This was, and remains, the best single source for finding out how to attach and remove groups that will protect reactive parts of your molecule until they're ready to be unveiled. Organic chemists spend a fair amount of time using these, especially for things like amines and hydroxyl groups, which are liable to become personally involved in all sorts of reactions if they're not restrained.

In my first encounters with these, I got the (completely mistaken) impression that all protecting groups tended to have specific recipes, precisely targeted for their removal. Methoxymethyl ether group to take off? Reach for the zinc bromide! Pivaloyl ester? Methyllithium! And so on. There was page after page of this sort of thing.

And it's not like those are poor choices, to be sure. I've used that methyllithium one myself, although not since about 1988. But zinc bromide isn't called for because of its essential zinc bromidey properties, it's called for because it's a Lewis acid, and just about any Lewis acid will take off a MOM group. Some will be faster than others, some might do things to the rest of your molecule which others wouldn't, but they'll all get around to cleaving your methoxymethyl ether. As will good old protic acids - aqueous hydrochloric will take one off just like it was 1895 again, if the rest of your molecule can stand it.

Learning all this, which I did in my later undergraduate years, was a good way to start appreciating the mechanistic side of organic chemistry. There really aren't that many reactions, no matter what poor sophomores think while they memorize page after page of them. Organic chemistry isn't zoology. And it also hit me, after a while in graduate school, that the claim of a new, mild, wonderful way to remove a given protecting group was a pretty good method to get a paper published, which might - just might - have something to do with their proliferation.

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

November 5, 2004

A Visit To Academia

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Posted by Derek

I gave a talk on drug discovery at a local university yesterday, which was an interesting trip. The labs were in a new building, and were quite nice. (I hope that Duke has renovated the labs I worked in during grad school, but I haven't heard that they have. . .if not, they must be getting pretty ratty by now. I did my part.)

I presented an older project from my work, one that we're not interested in pursuing any more, naturally. After telling them that I'd been doing this sort of thing for fifteen years without discovering any drugs, I said that I would be better suited for a talk about how not to discover drugs, but then went into the reasons why this is a pretty typical record.

I had some good questions at the end: How did we know when to stop making more compounds, someone wanted to know. How many peopel worked on it, total? How much did I estimate that whole thing must have cost? Did we know anything about what other companies were doing while the work was going on? Some of those are surprisingly hard to give a good answer to, when you try to account for all the work and expense put in by support groups that were working on several projects at once.

And had I ever thought about going into academics instead of industry? Oh, yes indeed. That had been my goal up through the first part of grad school, but a good close look at academia made me realize that the choice was harder than I'd thought. . .

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

November 3, 2004

Don't Ask; Just Trade

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Posted by Derek

At the risk of perpetuating the idea that my support of Bush was purely economic, it's worth noting that his re-election had an immediate impact on the pharmaceutical stocks.

The exception was the stock of companies closely identified with stem cell research. I should have gone short, darn it all. You have three reasonably pure plays in that category: Geron, Stemcells, and Aastrom, and they all got gonged today. (Likewise, they'd all been rising as the possibility of a Kerry win increased.)

And that's fairly silly. The Bush administration's stem cell policy (which I oppose), is to restrict public funding for research in the area. With private money, you can do what you want to do, and guess what? The biotech industry is the very definition of "private money." You could argue that the restrictions on NIH funding hold back the whole field (which is surely the case), making it less likely that commercial applications will be coming soon. But perhaps taking academia partly out of the game increases the chance that a major discovery would be completely owned by a company, rather than in-licensed.

At any rate, it's not like all three companies are focused on embryonic stem cell research. They just trade as if they were. Aastrom stock, for example, has been jerked around for years by clueless traders who don't bother to read the company's own press releases, which clearly state that they use only adult-derived stem cells. You know, the kind with no research restrictions on them? Ah, the efficient market.

Comments (2) + TrackBacks (0) | Category: Business and Markets

November 2, 2004

Let's See What the Sharks Think of These Steaks!

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Posted by Derek

I assume that anyone reading this blog today must be looking for something else besides election news or leaked exit poll numbers. How about some drug industry stuff? That I have, but it isn't good. Monday's Wall Street Journal brought a disturbing story about some leaked e-mails and internal memos from Merck and its troubles with Vioxx.

This piece, by Anna Wilde Matthews and Barbara Martinez, led to Merck's stock taking a terrible beating in today's trading, and it's pretty damned easy to see why. If these items are correct, and I've no reason to think that they aren't, Merck is in even bigger trouble than I thought. And believe me, that's really saying something.

It appears that prominent people inside the company not only thought early on that Vioxx had cardiovascular liabilities, but then did everything they could to divert attention and keep the drug on the market for as long as possible. Says the Journal story:

A Merck internal marketing document reviewed by The Wall Street Journal, addressed to "all field personnel with responsibility for Vioxx," provided an "obstacle handling guide." If a doctor said he was worried that Vioxx might raise the risk of a heart attack, he was to be told that the drug "would not be expected to demonstrate reductions" in heart attacks or other cardiovascular problems and that it was "not a substitute for aspirin." This wasn't a direct answer.
One training document is titled "Dodge Ball Vioxx" and consists of 16 pages. Each of the first 12 pages lists one "obstacle," apparently representing statements that might be made by a doctor. Among them are, "I am concerned about the cardiovascular effects of Vioxx" and "The competition has been in my office telling me that the incidence of heart attacks is greater with Vioxx than Celebrex." The final four pages each contain a single word in capital letters: "DODGE!"

There's more, including incidents of Merck coming down hard on academic researchers who presented negative appraisals of the drug. They seem to have gone way over the line - at least, what should be the line - in trying to protect their blockbuster drug. It's ugly and it's disappointing, because I always had a high opinion of the company. This is just the kind of thing that gives my industry a sleazy reputation, and it infuriates me to see how much of it can be deserved.

Naturally, Merck says that the statements in the article are taken out of context. Perhaps some of them are, but it would have to be a pretty unusual context for this stuff not be be what it looks like. And what it looks like is blood in the water for the lawyers, who will now go even more beserk than usual. Who could blame them? Who knows what other things might turn up in discovery proceedings, if goodies like this are already available?

No, I already thought that Merck was in major trouble, but this is going to be one for the record books. Merck is going to be out many, many billions of dollars, far more than they ever made from Vioxx itself. I don't see how the company gets out of this without terrible damage, with most of it done to the cheers of an angry crowd. It's sad, because in many ways Merck has been a great company that's done a lot of good in the world. But not always, and not this time.

Merck has a lot of very bright, very competent, very hard-working researchers. But trouble that's coming is going to lay waste to the good and the bad, the innocent and the guilty. Who will be spared?

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Why Everyone Loves Us

November 1, 2004

Now With The Great Taste of Fish

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Posted by Derek

You'll notice a new design here this morning - the Corantean Heirarchy is switching everyone over to a newer template. You can now adjust the text size, for example, which is something I know a lot of people have asked for (in both directions.) And if you get the blog by e-mail, you can now subscribe to specific categories of posts (or, more to the point I suppose, specifically leave some categories out!)

Let me know how things are working, and if you have some other features that you'd like to see. Other than the content of the posts, anyway - unfixable, that is.

Comments (5) + TrackBacks (0) | Category: Blog Housekeeping