About this Author
College chemistry, 1983
The 2002 Model
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: email@example.com
February 27, 2009
You don’t often get to see the sort of fistfight that’s detailed in the latest issue of Organic Process Research and Development. Patents whose procedures are hard to reproduce are familiar to every industrial chemist, unfortunately, but coming across one that seems completely mistaken in its most important details is rare. And this is the first time I’ve seen one of these dragged out into the open literature for a give-and-take with the original authors about whether they’re delusional or not. (The editors of the journal seem to be in new territory themselves on this one).
I should add here that the great majority of patent preps I’ve followed have worked pretty much as described, and I don’t think that my success rate in reproducing them is any worse than procedures from the chemical journals. Some journals more than others, of course, (another topic!) but OPRD is known to be very, very reproducible indeed. As it should be: it’s a journal for process chemists, whose livelihood is refining chemical routes until they’re scalable, economical, and (very importantly) until they work exactly the same way every time they’re run.
So here’s the situation. In 2007, the journal published a paper by a group from Dr. Reddy’s Laboratories, a large Indian company that does both generic drugs and has their own drug discovery operation. (There are, I should note, some academic co-authors who seem to have completely disappeared during this current food fight). The paper covered a synthesis of S-citalopram, and it caught the attention of the process chemists at Lundbeck, in Denmark. And well it might – citalopram (Celexa and other brand names), an antidepressant, was discovered there in the late 1980s, and has been generic since 2003.
The original paper (Eliati et al.) described a new alkylation reaction route to produce a key intermediate and a resolution of it (and of citalopram) into pure enantiomers by forming chiral salts. So far, so good – these sorts of things are the heart of process chemistry, and entirely appropriate for a paper in OPRD. But only if they work.
The Lundbeck group (Dancer and de Diego), had tried that exact resolution of citalopram many times themselves, though, without success, so they were rather taken aback to see it published as working just fine. They detail their attempts to reproduce the Eliati procedure, and demonstrate in great detail that it indeed does not work as written. I won’t go into their experimental work, which is very extensive and painstaking, but nothing the Lundbeck team could do resulted in anything better than a 55:45 mixture, which is a rather poor substitute for a pure compound. Midway through their paper, they start putting the word “resolution” in quotation marks when discussing the Eliati procedure, and the arm’s-length-and-holding-the-nose attitude is very successfully conveyed. The phrases “enormous disparity”, “effectively impossible”, “extremely unlikely”, and “not feasible in any meaningful, practical sense” all make appearances.
They also were surprised at the alkylation reaction reported in the Eliati paper, which is the only one of its kind reported in the literature – well, other than a patent by the same team from Dr. Reddy’s, that is. The weird thing about it is that it uses 3-chloropropylamine, apparently as the isolated free base. My chemistry audience will now be raising their eyebrows, because this is not a compound that you’d expect to be very happy as anything but a salt. It should, in fact, start reacting with itself quite vigorously, with plenty of HCl being given off in the process. But the Eliati procedure doesn’t have enough base to allow for anything else, and they use (supposedly) 12 grams of the stuff in 2.5 mL of DMSO. Since no paper or patent has ever reported isolation of this free base, it’s a rather odd compound to drop into your manuscript without explanation.
Another example of the same reaction in the Eliati paper is even weirder. Not only do they use this never-before-seen chloropropylamine, but this time they do the reaction in acetone, at 60 to 65 degrees C, by first adding 7.5 grams of potassium t-butoxide to 40 mL of the acetone. Now that prep should get the attention of the organic chemists in the audience, because that sounds like an excellent way to make a bunch of hot polymerized gunk. For one thing, acetone boils at 56, so how you get it to 65 is a real stumper. And adding a strong base to it is a surefire way to deprotonate it and start the famous aldol condensation (and every other base-catalyzed ketone reaction you can think of, for that matter). The Lundbeck group tried it, out of sheer curiosity, and got:
”. . . a vigorous/violent reaction. . .with the formation of a quantity of a white solid. (It had) an odor of higher ketones/alkenes, and analysis by NMR indicated that it was a complex mixture of products, with peaks consistent with condensation products of acetone.
A solid majority of the chemists reading that sentence, you can bet, finished reading that and added a “No shit” to the end. This is the sort of thing a sophomore undergraduate should be able to spot, and my guess is that whoever reviewed the Eliati paper for OPRD has had some interesting correspondence with the journal. The resolution is one thing – that’s impossible to spot if you haven’t worked with that exact reaction. But this alkylation step is ridiculous.
The journal gave Eliati and co-workers a chance to respond to all this, and followed that with a last word from Dancer and de Diego at Lundbeck. These things are all published back to back; it's like watching a boxing match. The Dr. Reddy’s group runs up the white flag immediately on the chiral salt resolution, actually, agreeing that their published procedure doesn’t work. But they claim that a modified version of the procedure does work, and that they “inadvertently missed incorporating a few words in the text” of the article which would have made this clear. The Lundbeck group isn’t buying this for a minute. They point out that the manuscript would have been had to have been substantially reworked to make it into this different procedure, for one thing. And even worse, the details of it as reported by Eliati are internally inconsistent, with the masses and ratios not even adding up. And finally, they report their own attempts to reproduce the new procedure, and find that it, too, is basically impossible.
And as for the alkylation, Eliati et al. claim that if you work quickly, you can use the chloropropylamine free base as they described. They also present a table showing how long it lasts under different conditions and in different solvents, and claim to have done the best variation of the reaction on a six-kilo scale. The acetone reaction, they admit, wasn’t as clean, but they didn’t spend much time talking about that because their “aim was to isolate the desired product instead of the aldol product.” Dancer and de Diego aren’t very happy with that either, continuing to insist that the acetone procedure is “completely unworkable”. As for the chloropropylamine, they welcome the clarifications in the second Eliati paper, but point out that said details contradict themselves at one point, and at any rate, none of them are to be found in the corresponding Dr. Reddy’s patent application, which continues to talk about using only the free base, and (on top of everything else) in a way that makes no sense.
The final Lundbeck reply has a telling line in the acknowledgements, which is, in its way, even more pointed than anything else in their paper: “One of us (R.J.D.) thanks Sir John Cornforth for inspiration derived from a series of his articles in a similar case some years ago.” That’s the famous “Some Comments on a Paper by Samir Chatterjee” affair, Tetrahedron Letters 1980 709 and 1982, 2213. Cornforth completely demolished some heterocyclic chemistry work by the unfortunate Chatterjee, pointing out by several lines of evidence that the whole thing had to have been faked. Name-dropping this example is about as direct a statement of your opinion as the scientific literature will allow. . .
+ TrackBacks (0) | Category: Chemical News | Drug Development | The Dark Side | The Scientific Literature
February 26, 2009
There are reports this morning that the FDA is halting further review of drug applications from one of the largest generic drug manufacturers, India's Ranbaxy. It appears that some test results submitted to the agency have been found to be falsified. Update: here's the FDA's complaint (PDF).
I'm not seeing any details on what sorts of numbers look to have been cooked, or how the FDA caught on - more may come to light later. But it's for sure that this is trouble no company needs, and behavior no company should engage in. It's going to be especially hard in this case, because Ranbaxy (and India) have been trying to prove themselves as major, trustworthy players in the industry. I would have put the company in that category already, unfortunately, until this.
But it's important to remember that US companies have had their own compliance issues with manufacturing over the years - ask Schering-Plough about that, among others. Until we have more details about what's going on, I think it would be prudent to hold off on the "see what those cheap foreign plants will try to get away with" rhetoric. Who knows, that may come later.
+ TrackBacks (0) | Category: Current Events | The Dark Side
Metformin, now there’s a drug story for you. It’s a startlingly small molecule, the sort of thing that chemists look and and say “That’s a real drug?” It kicked around in the literature and the labs in the 1960s, was marketed in Europe in the 1980s but was shopped around in the US for quite a while, partly because a lot of people had just that reaction. (It didn't help that a couple of other drugs in the same structural class turned out to cause lactic acidosis and had to be pulled from use). Bristol-Myers Squibb finally took metformin up, though, and did extremely well with it in the end under the brand name Glucophage. It’s now generic, and continues to be widely prescribed for Type II diabetes.
But for many years, no one had a clue how it worked. It not only went all the way through clinical trials and FDA approval without a mechanism, it was nearly to the end of its patent lifetime before a plausible mechanism became clear. It’s now generally accepted that metformin is an activator (somehow, maybe through another enzyme called LKB1) of adenosine monophosphate kinase (AMPK), and that many (most?) of its effects are probably driven through that pathway. AMPK’s a central player in a lot of metabolic processes, so this proposal is certainly plausible.
But never think that you completely understand these things (and, as a corollary, never trust anyone who tries to convince you that they do). A new paper in PNAS advances the potentially alarming hypothesis that metformin may actually exacerbate the pathology of Alzheimer’s disease. This hasn’t been proven in humans yet, but the evidence that the authors present makes a strong case that someone should check this out quickly.
There’s a strong connection between insulin, diabetes, and brain function. Actually, there are a lot of strong connections, and we definitely haven’t figured them all out yet. Some of them make immediate sense – the brain pretty much has to run on glucose, as opposed to the rest of the body, which can largely switch to fatty acids as an energy source if need be. So blood sugar regulation is a very large concern up there in the skull. But insulin has many, many more effects than its instant actions on glucose uptake. It’s also tied into powerful growth factor pathways, cell development, lifespan, and other things, so its interactions with brain function are surely rather tangled.
And there’s some sort of connection between diabetes and Alzheimer’s. Type II diabetes is considered to be a risk factor for AD, and there’s some evidence that insulin can improve cognition in patients with the disease. There’s also some evidence that the marketed PPAR-gamma drugs (the thiazolidinediones rosiglitazone and pioglitazone) have some benefit for patients with early-stage Alzheimer’s. (Nothing, as far as I’m aware, is of much benefit for people with late-stage Alzheimer’s). Just in the past month, more work has appeared in this area. The authors of this latest paper wanted to take a look at metformin from this angle, since it’s so widely used in the older diabetic population.
What came out was a surprise. In cell culture, metformin seems to increase the amount of beta-amyloid generated by neurons. If you buy into the beta-amyloid hypothesis of Alzheimer’s, that’s very bad news indeed. (And even people that don’t think that amyloid is the proximate cause of the disease don’t think it’s good for you.) It seems to be doing this by upregulating beta-secretase (BACE), one of the key enzymes involved in producing beta-amyloid from the larger amyloid precursor protein (APP). And that upregulation seems to be driven by AMPK, but independent of glucose and insulin effects.
The paper takes this pretty thoroughly through cell culture models, and at the end all the way to live rats. They showed small but significant increases in beta-secretase activity in rat brain after six days of metformin treatment. And the authors conclude that:
Our finding that metformin increases A-beta generation and secretion raises the concern of potential side-effects, of accelerating AD clinical manifestation in patients with type 2 diabetes, especially in the aged population. This concern needs to be addressed by direct testing of the drug in animal models, in conjunction with learning, memory and behavioral tests.
Unfortunately, I think they’re quite right. Update - in response to questions, it appears that metformin may well cross into the brain, presumably at least partly by some sort of active transport. There's some evidence both ways, but it's certainly possible that relevant levels make it in. With any luck, this will be found not to translate to humans, or not with any real clinical effect, but someone’s going to have to make sure of that. For those of us back in the early stages of drug discovery, the lesson is (once again): never, never think we completely understand what a drug is doing. We don’t.
+ TrackBacks (0) | Category: Alzheimer's Disease | Diabetes and Obesity | Drug Industry History | Toxicology
February 25, 2009
I wanted to link to this excellent article by Felix Salmon over at Wired. He's talking about the mathematical formula that convinced many people on Wall Street that they'd figured out how to price out correlated risks in debt securities. As we all now know, they'd done no such thing, even though trillions of dollars ended up riding on the whole idea.
The article's well worth reading just on those terms. But it's also worth thinking about for what it says about other fields where the risks - and the correlations between different risks - can't be well measured. Such as drug discovery and development! Many examples in Salmon's article can be extended directly to our own industry: what are the risks of each compound in Company X's pipeline failing? If a compound with a similar mechanism wipes out over at Company Y, how have the odds now changed? What about patent risks - if a Supreme Court decision makes everyone rethink issues of infringement or obviousness, how correlated are the patent-busting exposure around the industry? And so on. . .
The difference is that we haven't (quite) convinced ourselves over here that we've got it all figured out, and we haven't issued billions of dollars in derivative securities on top of our individual drug development programs. Not yet, anyway. But if you come away from a study of the current situation with a mistrust of any formula that people try to use to quantify complex systems down to one easy-to-use number, well, you've come out ahead.
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Have you ever worked for a company with its own corporate anthem? It would probably have to be a fairly large outfit; I don’t think a smaller shop would be able to afford such a thing, even if they somehow decided that they needed one. (Here’s some advice: if your small or medium-sized company rolls out its own song, strongly consider hitting the exits if you can. That’s the sort of mindless expenditure that only a behemoth can get away with).
I’ve encountered one of these, in one of my former positions. We were having some big site-wide meeting, and one of the honchos introduced the video clip. There are whole agencies who do these things – they write the songs, hire people to sing them, produce the video, and so on, and the product of one of these bizarre production companies was what we got to see.
And what a sight it was. A perfectly calibrated multiethnic assembly began to belt out our new company song with verve and enthusiasm. There were plenty of solo shots and different camera angles. It was all about dreams and teams, visions and decisions, exceeding and succeeding. The singers grinned, looked confidently up into the future, and joined hands as they got to the chorus. I watched all this with mounting dismay and horror, wanting to clap my hands over my ears, both to shut out the music and to keep my soul from trying to flee my body via my Eustachian tubes.
I don’t think that this was the reaction the song was meant to elicit, but I didn’t seem to be alone. As I left the auditorium with some of my fellow chemists, we speculated on whose idea this anthem might have been, how much it had cost, on whether the firm that produced it was from North Korea or not, and wondered how the experience of listening to it might have affected our lifespan and fertility. One of my group said that there surely must have been better songs available, and suggested that he personally would have been much more motivated by AC/DC’s “Highway to Hell”.
I had to agree; that would have done it for me, too. I started imagining a re-take of the video: the same blue backdrop, one of our executives striding out, giving the camera a manly smile, and saying: “Yes, here at _____ Pharmaceuticals, we truly are on a Highway To Hell. Won’t you join us?” The same happy singers would come streaming out from both sides, swinging into the chorus. . .oh, that would have been much better. And overall, rather more accurate than all that “driven by our vision” stuff, too, now that I think about it.
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February 24, 2009
Medicinal chemists spend a lot of their time exploring and trying to make sense of structure-activity relationships (SARs). We vary our molecules in all kinds of ways, have the biologists run them through the assays, and then sit down to make sense of the results.
And then, like as not, we get up again after a few minutes, shaking our heads. Has anyone out there ever worked on a project where the entire SAR made sense? I’ve always considered it a triumph if even a reasonable majority of the compounds fit into an interpretable pattern. SAR development is a perfect example of things not quite working out the way that they do in textbooks.
The most common surprise when you get your results back, if that phrase “common surprise” makes any sense, is to find that you’ve pushed some trend a bit too far. Methyl was pretty good, ethyl was better, but anything larger drops dead. I don’t count that sort of thing – those are boundary conditions, for the most part, and one of the things you do in a med-chem program is establish the limits under which you can work. But there are still a number of cases where what you thought was a wall turns out to have a secret passage or two hidden in it. You can’t put any para-substituents on that ring, sure. . .unless you have a basic amine over on the other end of the molecule, and then you suddenly can.
I’d say that a lot of these get missed, because after a project’s been running a while, various SAR dogmas get propagated. There are features of the structure space that “everybody knows”, and that few people want to spend their time violating. But it’s worth devoting a small (but real) amount of effort to going back and checking some of these after the lead molecule has evolved a bit, since you can get surprised.
Some projects I’ve worked on have so many conditional clauses of this sort built into their SAR that you wonder whether there are any boundaries at all. This works, unless you have this, but if you have that over there it can be OK, although there is that other compound which didn’t. . .making sense of this stuff can just be impossible. The opposite situation, the fabled Perfectly Additive SAR, is something I’ve never encountered in person, although I’ve heard tales after the fact. That’s the closest we come to the textbooks, where you can mix and match groups and substituents any way you like, predicting as you go from the previous trends just how they’ll come out. I have to think that any time you can do this, that it has to be taking place in a fairly narrow structure space – surely we can always break any trend like this with a little imagination.
Another well-known bit of craziness is the Only Thing That Works There. You’ll have whole series of compounds that have to have a a methyl group at some position, or they’re all dead. Nothing smaller, nothing larger, nothing with a different electronic flavor: it’s methyl or death. (Or fluoro, or a thiazole, or what have you – I’ve probably seen this with methyl more than with other groups, but it can happen all over the place). A sharp SAR is certainly nothing to fear; it’s probably telling you that you really are making good close contacts with the protein target somewhere. But it can be unnerving, and sometimes there’s not a lot of room left on the ledge when you have more than one constraint like this.
Why does all this go on? Multiple binding modes, you have to think. Proteins are flexible beasts, and they've got lots of ways to react to ligands. And it's important never to forget that we can't predict their responses, at least not yet and not very well. And of course, in all this discussion, we've just been considering one target protein. When you think about the other things your molecule might be hitting in cells or in a whole animal, and that the SAR relationships for those off-target things are just as fluid and complicated as for your target, well. . .you can see why medicinal chemistry is not going away anytime soon. Or shouldn't, anyway.
+ TrackBacks (0) | Category: Drug Assays | In Silico | Life in the Drug Labs
February 23, 2009
This piece over at Science magazine's "The Gonzo Scientist", brought back some memories. John Bohannon, in the midst of an investigation of truffles, tried an experiment on some party guests: rank a series of five patés according to taste. There were three authentic ones, two fake ones (liverwurst and whipped Spam), and. . .dog food.
He did tell people that dog food was one of the choices. Interestingly, although it ranked last in the taste test, people were no better than chance at identifying it as such. Perhaps they expected it to taste better than it did? But the reason this made me smile was thinking about the usual behavior of scientists and engineers down by the coffee machine. You know what I'm talking about - put anything down there, and people will eat it. It's a standard way of clearing out dessert-like things from home that you don't want around the place; take it to work and it'll disappear.
Well, I saw that put to the test once at a former company of mine. One of the freer spirits down the hall put out a bowl of chocolate-flavored hamster treats and sat back to watch the results. Unlike the dog-food experiment, he did not inform his subjects - but in his defense, he told me that he'd tried one himself, and that although they were somewhat gritty, he'd had worse.
Results? The hamster treats disappeared, of course. I'm just glad he didn't press on with this line of research - and as for me, I made sure never to eat anything left by the coffee machine at that end of the hallway. . .
+ TrackBacks (0) | Category: Life in the Drug Labs
This article from the San Jose Mercury News has gotten a lot of attention for its take on the Roche-Genentech struggle. The reporter, Steve Johnson, is asking if all the concerns about Genentech's fate are overdone.
It's true that the precious-unique-culture stuff can be overemphasized. Roche has indeed been insisting that they want to preserve Genentech's entrepreneurial spirit (although, to be honest, they'd say that no matter what they were really thinking - what are they going to do, say that they really just want all the Avastin revenue and whatever else is high up in the pipeline?) And, as the article correctly points out, there have been any number of good-sized biotech outfits taken over by Big Pharma over the years.
But what worries me a bit is what's happened to some of those biotechs. It really is rare, from what I can see, for a company's culture to stay the same after something like this happens. It's a bit like those singers who make it big from obscurity; you read these articles saying that they're just the same small-town person that they always were. Right - that would be the least likely outcome of them all.
The thing is, the atmosphere of the acquiring company is going to seep in, no matter what. The new projects are going to be approved using the processes of the larger company, aren't they? They'll be expected to fit into a new, larger picture, and to find their place. And the compounds that advance will advance against the larger company's criteria, not the ones in place under the old regime.
Those are just the direct effects on research. What might be a larger difference is a psychological one. As a stand-alone company, even one the size of Genentech, you live by your own wits, but that changes. As part of a larger company, you know that there are other projects out there, other divisions, and that some of these will be expected to pick up the slack now and then. It's a big company, after all. It'll keep going, even if you don't deliver this year. Right? That's actually one of the trickier parts about running a company with a lot of sites and research areas - the inevitable frictions when one group or another feels (sometimes correctly) that they're being leaned on more than those lazy bums over in XYZ, who haven't delivered a clinical candidate since (fill in the year).
At more than one of my previous jobs, I've heard a lot about a "sense of urgency", and how desirable that is. (That's mostly true, although too much of it can perhaps cause you to do something stupid under time pressure). Overall, it really does help to know that you really do have to deliver, that there's no net down there, no one waiting to cushion the blow. It doesn't make things fun, not necessarily, but it does make them more productive. Remember Samuel Johnson's remark about the minister-turned-forger William Dodd: "Depend upon it, Sir, when a man knows he is to be hanged in a fortnight, it concentrates his mind wonderfully."
Unfortunately, I think the key line in the Mercury News piece is this one:
Besides, Genentech scientists don't have a lot of other employment options these days, according to Rodman & Renshaw analyst Christopher James. "There would be more of a concern in a market where there were a lot of opportunities for people to leave," he said.
There's the rub, all right. . .
+ TrackBacks (0) | Category: Business and Markets | Who Discovers and Why
February 20, 2009
I'm taking the day off from cranking out the medicines of tomorrow (OK, the day after tomorrow), so there will be no post today.
I did want to add something about yesterday's post on the La Clair/hexacyclinol controversy. I'd like to ask that people not fill up the comments with ad hominem remarks or potentially libelous statements about La Clair himself. I don't mind saying that the evidence so far makes it very hard for me to believe his original paper, and I also have to say that I haven't seen any convincing explanations for all the discrepancies that have turned up. And I think that those opinions are shared by many people who've followed the story.
But let's keep it on a scientific plane, if possible. Opinions on NMR spectra and the like are one thing, but personal insults are another, and those we don't need. I try not to have to go in and hose out the comments sections around here.
+ TrackBacks (0) | Category: Blog Housekeeping | Chemical News | The Scientific Literature
February 19, 2009
Remember hexacyclinol? Some readers are probably groaning and thinking “Oh, yes, indeed”, which may make up for the ones who are saying “Remember what?”
Hexacyclinol is a complex natural product, but after that statement the arguing begins. James La Clair published a synthesis of it in 2006 in Angewandte Chemie, one of the most prestigious chemistry journals, but the reception of the paper did nothing to help the prestige of either La Clair or the journal. Readers immediately seized on odd spectral data and experimental details to ask whether the molecule had been made at all and just how well the manuscript had been refereed.
The story got even messier later in the year when synthetic organic chemist Scott Rychnovsky weighed in with a paper suggesting that the structure of the natural product had been misassigned to start with. This was followed by a synthesis by John Porco and his group of his proposed structure, which turned out to match the NMR spectra of the original natural product. Since they also had an X-ray crystal structure, you would think that this would have ended the argument, at least at the level of what hexacyclinol looks like. The argument about what La Clair actually made, though, continued. And La Clair himself suggested that he and Rychnovsky had made two different molecules that just happened to have very similar NMR spectra.
Now a paper in Organic Letters is trying to clear that part of the story up, saying that ” indeed, the possibility that two molecules as complex as 1 and 2 may have indistinguishable NMR spectra carries an uneasy feel.” The authors, Giacomo Saielli and Allesandro Bagno from the University of Padova, return to the two proposed structures and calculate both their carbon and proton NMR spectra using what appear to be the best methods available for estimating their shifts and coupling constants.
The second structure fits much, much better, and the authors conclude that there is “hardly any doubt” that it’s the correct structure for hexacyclinol. In fact, they go further:
”The structure of hexacyclinol is confirmed to be 2. Furthermore, if 1 had been synthesized or was formed from an unforeseen reaction, its NMR spectra are sufficiently different from those of 2 as to guarantee their distinction.”
Note the “if it had been synthesized”. As far as I can tell, the remaining questions in this case aren't chemical. They're psychological. The original Ang. Chem. synthesis is certainly incapable of generating the real structure of hexacyclinol, but it also appears incapable of making the structure it claims to have made. Taken together with its original odd features, you have to wonder just what it was: a hoax? An odd and pointless work of fiction? Self-deception? We’ll probably never know. All we know is what it isn't.
For more reactions oto this latest news, see The Curious Wavefunction and The Chemistry Blog.
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February 18, 2009
+ TrackBacks (0) | Category: Book Recommendations | Business and Markets
When I joined the Wonder Drug Factory in late 1997, you still had to buy chemicals by writing down the name and catalog number on a form (and press hard; it was one of those multicolor triplicates). I thought that was pretty primitive then, since at my previous company we’d already gone to electronic ordering (clunky, especially in retrospect, but a lot better than anything involving blue, white, and yellow forms). But to find out where to buy the chemicals you wanted – now that was a challenge.
ChemSources was the usual solution. That was (is, I guess) a large volume containing compounds indexed by name and formula, with the suppliers listed for each. There was a red one for domestic suppliers, and a similar-sized blue book for international ones. And although it came out regularly, it was perforce always out of date. How could it not be? The suppliers changed their catalogs constantly. For that matter, the list of suppliers changed constantly. It wasn’t unusual to look up a compound, find its only commercial source was some little outfit you’d never heard of, and find on tracking them down that they’d gone out of business the previous year.
No one does it that way any more, of course, and good riddance. ChemSources appears to still be in business, and you can even get their bound volumes for your shelves. But why would you do such a thing? Even they offer online searching - well, for a subscription fee. But why would you do that? There are free sources for basically the same information. If you just want data on some compound and where it might turn up, ChemSpider is a good place to look. And if you want supplier information, eMolecules looks like the place to go. Their model is "basic search for free", and if you want pricing, export of data, or integration with your in-house databases, you can sign up for their "plus" service and pay fees.
And that's pretty reasonable, because I get a lot of use out of the free service, myself. I can see prices in my company's in-house ordering software. But I'm not one of the most price-conscious chemical consumers out there, since I'm mostly ordering small quantities of a lot of different things. As long as someone isn't egregiously ripping me off, I'm fine (and that's what our Purchasing department is there to check on, anyway, and don't they just love me over there). One of the things that I enjoy about eMolecules, though, is that they help me figure out what a lot of these little bar-coded vials are. There are a lot of suppliers that will send you ten milligrams of stuff with no real label on the vial, just an eight-digit number or the like, which isn't much help. If you don't label them right then - which often involves loading a CD that they shipped with the vials - you can be puzzled in a few weeks or months when you need the stuff again.
But the eMolecules folks have all these people in their files - Life, ChemDiv, Asinex, Specs, ChemBridge, and the other members of the catalog-number-only club. The search isn't perfect (for one thing, they're missing a fair bit of the corresponding CAS numbers to search by), but it's a lot better than anything else I've come across for free.
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February 17, 2009
Carbon 12, nitrogen 14 – for that matter, hydrogen 1. Everyone who’s had to study even a bit of chemistry has had to learn the molecular weights of the elements, figure molecular weights from formulas, and so on. But these numbers aren’t quite as round and even as they look, and the consequences of that are sometimes surprising. And at the moment, at least three companies are trying to turn the whole idea into a huge amount of money.
My scientific audience will have guessed immediately that I’m talking about isotopes (although some of them may well be wondering where the pile of money comes into it). For those who don’t make a living at this sort of thing and have put such topics out of their minds, it’s the number of protons in an atom’s nucleus (the atomic number) that determines what sort of element it is. Carbon, for example, always has six protons. But there are neutrons in there, too, and those can vary a bit. Six protons and six neutrons gives you a nucleus of carbon-12, which is the most common. But one out of every hundred or so carbon atoms has seven neutrons instead of six: C-13. That’s a perfectly stable isotope of carbon, and is much beloved by chemists for its behavior in NMR experiments. If you push that neutron count too far, though, you get unstable radioactive nuclei. That’s where the famous carbon-14 comes into the picture (six protons, eight neutrons). You can have carbon-11, too, although it’s pretty hot stuff. Hydrogen, for its part, has the usual one-proton nucleus in its most common form, a one-proton-one-neutron stable form called deuterium, and a radioactive form with two neutrons called tritium, found in isotope labs and the innards of hydrogen bombs).
Radioactive isotopes have a long history in medicine and biochemistry, both as therapeutic agents (for cancer) and as tracers. But what about stable isotopes? Until recent years, not as much. But modern mass spectrometry machines are so good at what they do that they’ve eaten into a lot of the applications that used to be reserved for radioactive isotopes – more on that in another blog post; there are some ingenious tricks there. And those three companies I mentioned are trying to take advantage of yet another property, known as the kinetic isotope effect.
Imagine a bond between a hydrogen and a carbon as being between two metal balls, one of them twelve times as heavy as the other, connected by a spring. This is about as simplistic a picture of a carbon-hydrogen bond as you could possibly come up with, but for this purpose that model works disconcertingly well. Imagine then replacing the smaller ball with one that weighs twice as much as the original one; that’s a replacement of hydrogen with deuterium. Now, how will the behavior of that springy system change?
Well, that’s sophomore physics, weights and springs, and that’ll tell you that it’s now harder to twang the second system around. We see that exact effect in chemistry. A carbon-deuterium bond breaks about six or seven times slower than a carbon-hydrogen bond under room-temperature conditions. So where exactly is the big money in this effect?
Consider what happens to a drug when it’s ingested. Through the gut wall it goes, into the hepatic portal vein, and directly into that vast shredder we know as the liver. Various enzymes go to work tearing your unrecognized drug structure apart, the better to sluice it out through the kidneys as quickly as possible. And there’s the opportunity: a great many of those enzymatic reactions involve breaking carbon-hydrogen bonds. What if they were deuteriums instead?
That’s what Auspex, Protia, and Concert Pharmaceuticals are all working on. They’re taking existing drugs, whose metabolic fates are known, and battening their structures down with deuterium atoms in hopes of improving their half-lives and general behavior. And thus far, the idea seems to be working out. Auspex announced last fall that they'd seen good results (PDF) in the clinic with a deuterated version of venlafaxine (brand name Effexor, a well-known antidepressant. Concert, for their part, has announced that they've improved the antibiotic linezolid, sold as Zyvox. Protia - well, as far as I can see, Protia has been very quietly filing patents on deuterated versions of every big-selling drug that they can think of. What they're doing in the lab seems to still be under wraps.
Is this going to work? Good question. To a first approximation, you'd think it probably would, particularly for drugs whose main liabilities are poor pharmacokinetics (or side effects driven by a particular metabolite). But there are complications. For one thing, deuterium is not completely innocuous in vivo. I strongly doubt that the dosages of deuterated pharmaceuticals could present any kind of problem, but if you load up a higher organism with exchangable deuterium, trouble ensues. For humans, it would seem that you could, in theory, go a week or so on a few liters a day of straight deuterated water before you'd have to worry, which is nonetheless an experiment that I would strongly discourage. So the amount of deuterium picked up through metabolism of a prescription drug should have no effect - but there's always the possibility that the FDA, in its risk-averse mode, might make you jump through some extra hoops to prove that.
Another (much more real) risk is that the whole strategy will burn itself out. Clearly, the existing startups are working off the fact that no one has traditionally bothered to claim deuterated versions of their patented compounds. That is surely already changing, and if something hits the market it'll change big-time, reminiscent of Sepracor's old business model of grabbing unclaimed metabolites and enantiomers. And, of course, the three companies in this space are surely already throwing elbows into each other's IP space already.
But there's still a window of opportunity, and these folks are going for it. Isotope effects could end up being rather more immediately valuable than anyone ever knew. . .
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February 16, 2009
Today is a holiday in many workplaces around the US today, and so it is at mine. I'm home at stately Lowe Manor, breaking ice off the shady front steps and cleaning out the cage of my daughter's guinea pig. The comparatively relaxing (and comparatively nice-smelling) business of drug discovery will resume tomorrow, as will blogging. See everyone then!
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February 13, 2009
If you want a good example of the way that the popular media handle a drug discovery story, take a look at all the headlines this morning on the news of the sequencing of the common-cold rhinoviruses.
There are a couple of "Cure For the Common Cold Unlikely" ones, but most of the others seem to regard this as a big step forward. "Cure May Be Found", "Getting Closer" , "May Lead to Cure", "Could Help to Cure" - that's the sort of thing. The problem is, how many viral diseases can we cure? I mean, really cure with drugs after a person's been infected, wipe out and make go away? Right. Do I hear a zero? Viral diseases can be very difficult to get a handle on, because there aren't many moving parts in there. If none of them are amenable to small-molecule drug approaches, people like me are pretty well out of the game.
The best chance you have with a viral infection is with a vaccine. But what this genomics work is telling us, actually, is that a vaccine is going to be rather hard to come by. This paper sequenced ninety-nine different rhinovirus strains, and if there are that many, there are surely that many more. Or there will be, after the next cold season - just wait. These things are mutating all the time - which is, of course, why we get colds year after year. The team working on this project was able to bin the viral genomes into fifteen different classes, but what are we going to do, develop fifteen different (and simultaneous) vaccines? Against a scurrying, hopping, moving target like this one?
No, this is very interesting work, and it'll tell us a lot about how viruses do their nasty viral business out in the real world. But I wouldn't start throwing around the "C" word. All that can do is disappoint people, I'm afraid.
UpdateOK, so who's giving the wrong impression here? As per the comments to this post, here's one of the article's co-authors, Dr. Steve Liggett, as quoted in the New York Times:
"We are now quite certain that we see the Achilles' heel, and that a very effective treatment for the common cold is at hand," said Dr. Stephen Liggett, an asthma expert at the University of Maryland and co-author of the finding.
Say what? That's just a bizarre thing to say. But perhaps he was misquoted, because you can also find this, which seems to be a lot more grounded in reality:
There is hope that a careful study of the viral genomes will reveal one central point of attack that could be exploited by drug makers. "What we would like is a single Achilles' heel for all the viruses that we have found so far, and we could attack in that direction," Liggett said.
But the viruses are found to have impressive powers of change. The study shows that some human rhinoviruses result from the exchange of genetic material from two separate strains infecting the same person. Such recombination had not been thought possible for rhinoviruses.
That recombination is one reason why a vaccine against the common cold appears to be impossible, said Ann C. Palmenberg, director of the Institute for Molecular Virology at the University of Wisconsin, and lead author of the sequencing effort. The viruses just keep changing too much.
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February 12, 2009
Just ask La Jolla Pharmaceuticals, whose small stock is down about 90 per cent on the bad news. They follow a distinguished list of wipeouts in this area. Immunology is hard.
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As you may well have heard by now, Ben Goldacre over at Bad Science has been involved in a wonderful altercation with both the anti-vaccination people there and with one of London’s big talk radio stations, LBC. And yes, this is happening just as Andrew Wakefield, one of the originators of the whole MMR vaccine flap, is being accused of falsifying data to make his case.
The full story can be found on Goldacre’s blog; see the link above for a starting point. The short version: LBC allowed Jeni Barnett, an outspoken opponent of vaccination, to vent her views for some 45 minutes in a prominent time slot. As Goldacre points out, she seems to have covered every possible anti-vaccine trope, despite the fact that some of them were mutually contradictory and many of them made little sense to start with. The British media – many parts of it, anyway – has not covered itself in glory on the whole vaccine-risk story, and this latest outburst was too much for Goldacre to take.
He posted the entire audio of the LBC show on his website, and that brought on threats of legal action from the radio station. And that move, as anyone who’s hung around the internet can tell you, made sure that the audio was immediately scattered around the world, with commentary, transcripts, and plenty of bad publicity. (You can find plenty of links to all of it here; I’m late to this particular party myself).
Goldacre makes an important point, one that’s been made before but has to be kept in mind when you’re listening to the news coverage of any disputed issue. He quotes Jeni Barnett as:
”. . . explaining endlessly that all she wanted to do was “start a debate” (because in the media everything is 50:50, and the truth lies exactly half way between the two most extreme views)
He's right; you run into that sort of thing all the time – readers who’ve had occasion to deal with Intelligent Design people and other creationists will recognize it immediately. “Teach the controversy” "Let's hear both sides of the debate", and all that. It’s another example of the disconnect between science works (or should work) and the political and social arenas. There are some big differences in the way disputes are resolved.
One of them is that, to a certain degree, questions do not remain open in scientific debate in the same way they do in politics. Fistfights are currently erupting over whether Keynes had a point about deficit spending in a recession (and if he did, how much is appropriate and in what way). Huge, ever-inflamed arguments take place over welfare, regulatory policy, defense spending, and other perennials. There are more than two sides to these kinds of issues. But come over here to the scientific world, where gravity really does diminish as the square of the distance between two objects; bacteria really do cause infections; sodium really reacts with water and yes, living organisms do evolve and change over time. Proclaiming that you disagree with these things just because you don’t like them, just think that they’re wrong, or don’t happen to believe them will get you nowhere in scientific debate. (That’s as opposed to political or religious debates, where those are all-too-common starting points).
But, at the same time, every question in science is potentially open. Look at all those facts I listed above – you can find ways around all of them. Gravity stops behaving in a perfect inverse-square way close to large masses. Not all bacteria cause infections, of course, and not all infections are caused by bacteria - and some bacteria that might kill one person could cause no problems for someone else. Sodium doesn’t do anything spectacular at all when it’s in the plus-one oxidation state, and even the metal probably doesn’t do much when exposed to water at, say, three degrees Kelvin. And organisms evolve at startlingly different rates and through a variety of mechanisms.
These two simultaneous principles – that questions really do get answered, but that the answers are always open to question – are what puzzle a lot of people about science. And they don’t fit well with the way that many people are used to arguing about issues. They can dwell on the first point and whack the scientific community over the head for having closed minds and unchallenged dogmas, or dwell on the second and claim that hey, they're all unproven theories, and here are some more theories to put on the table while we're at it.
But if you’re going to challenge some science that we think we understand, you’re going to have to bring the data. The bigger the topic, the better the evidence you’re going to need. You can do it – all kinds of cherished theories have gone down – but it’s not easy. If you’re going to claim that evolution doesn’t happen, or that we’re thinking about it all wrong, you’d better have some really impressive evidence (and coming up with an alternative with the same kind of explanatory power would help, too). If you’re going to claim that vaccines do more harm than good, or that they’re the cause of a specific terrible condition, you’d better have the numbers to back it up, not a mish-mosh of talking points.
Einstein’s work, for example, has stood up against all comers, taking on all kinds of extraordinarily painstaking experimental tests and passing every single one of them. If you’re going to beat relativity, you’re going to have to show up with absolutely epic skills. And that brings up a last point. When Einstein explained Mercury’s orbit (and more besides), he didn’t come in proclaiming that Newton was an idiot and that he’d gotten it all wrong. Isaac Newton, though an exceptionally weird human being, was very far indeed from being an idiot. No, relativity shows how under “normal” circumstances, Newton’s gravitational laws work wonderfully. Then it shows under what conditions they go off track, and predicts when that will happen and exactly to what degree. If you’re going to proclaim any new way of looking at the scientific evidence, you’re going to have to show how your breakthrough allows for something new to be seen, and you’re going to have to call your shots and be ready for the experimentalists to have a crack at you.
I find all this wonderfully exciting, and I've devoted my career to it. But it doesn't necessarily make for a quick TV or radio segment that will bring in a big audience, stir up a lot of noise and chatter, and (most importantly) raise the advertising rates. For that, you want politics, religion, or some tasty mixture thereof. . .
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February 11, 2009
+ TrackBacks (0) | Category: Book Recommendations | Drug Development | Pharmacokinetics | Toxicology
For the last ten or fifteen years, untold amounts of time and money have been spent developing drugs to inhibit kinase enzymes. Just go take a look at KinasePro’s archives; that’ll give you the idea. Huge programs have been run at all the major drug companies, and any number of smaller ones have been founded just on the strength of one kinase inhibitor or another.
The enthusiasm isn’t hard to understand. For those of you outside the med-chem / biochem worlds, kinase enzymes are there to stick phosphate groups into other molecules, which is a very widely used signaling pathway. A phosphate completely changes the character of the part of a molecule where it’s attached, changing what other partners it will recognize and bind to. This takes place generally on to some sort of free OH group. That doesn’t narrow things down much, though, since there a lot of incredibly important small molecules with OH groups that get phosphorylated. Adding to the fun, several amino acids (serine, threonine, and tyrosine) have OH groups on them, and the means that nearly every decent-sized protein has plenty. The patterns of their phosphate groups turn their activities on and off, determine where they go and what they’ll recognize. It’s a major, major switching mechanism for protein activity – you can’t overstate its importance. Here's the classic family tree of the protein kinases, just to give you the idea. (And in case you’re wondering, there is indeed a whole different class of enzymes, the phosphatases, that take the things back off again - whole different bag of snakes, those guys).
There are hundreds and hundreds of kinase enzymes, and I think it’s safe to say that they’re involved in just about every important biochemical process you can think of. The downside of working on them is that, well, they’re involved in just about every important biochemical process you can think of. (Try this on for size, or this, to get the idea). How do you get them to do what you want?
Well, we’re still not sure about that. I go back far enough to remember when kinases were considered nearly impossible to work with as drug targets, because no one could figure out how you’d get selectivity. But once we figured out how to make molecules that recognized the “hinge” region common to most of these enzymes, the game was on. You can make blunderbuss molecules that inhibit dozens of enzymes at the same time, or (in some cases) you can narrow down on a mere handful, or on just one.
But how far do you want to go? That’s where we’re “over-asked”, as the German expression translates. The downstream effects of many of these enzymes are absolutely bewildering in normal cells, and the differences in disease states are even more of a tangle. It’s no surprise at all that most kinase inhibitors have shown up first in oncology, because that’s where you can get away with the most severe side effects. There are plenty of tempting opportunities in inflammation, diabetes, cardiovascular disease, and other areas, but those have been slower to come along.
The experience with the cancer-targeting drugs has been mixed. You have your Gleevec (imatinib) – pretty selective, works pretty well on a very limited group of patients. And you have your hand grenades, like Sutent (sunitinib) or Nexavar (sorafenib), which hit a lot of kinases and work (to some degree) on a lot of different things. But none of them are magic bullets, for sure. So do you want selectivity or not? The only answer we can offer is (still) “that depends”.
These days, there’s a distinct “kinase hangover” in the industry. It’s not as hot a field as it was. “Not again” is the usual feeling on seeing yet another patent or publication on yet another structure that inhibits XYZ kinase. It’s not as hot an area as it was a few years ago – the belief is that many of the best targets have either wiped out in the clinic, are being tried there now, or haven’t yielded reasonable chemical matter to even get there.
My guess is that we’re waiting, whether we know it or not, for our understanding of the biology to catch up. We have all these compounds, with all these different fingerprints, and we’ve generated this huge pile of mixed data that we can’t quite make sense of. That adds to the frustrated “been there” feeling. The cure for it is to have a better idea of what we’re doing and why, but that’s coming on much more slowly. And because that’s slow, the kinase field may never regain its hot status. But who knows, it may make it all the way to useful and valuable, bypassing “hot” completely.
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
February 10, 2009
The Wall Street Journal recently asked a whole list of CEOs , including Daniel Vasella of Novartis, for business book recommendations, and on the whole, it’s a saner selection than one might have feared (Peter Drucker, etc.)
Over at the Atlantic’s Business Channel (where I’m also contributing some occasional entries), a fellow blogger who operates under the name of “Harvey Wallbanger” noted that article and is in turn soliciting nominations for the worst business book. And yes, he opens with the grievously awful “Who Moved My Cheese”, which I was careful to stay ten feet away from at all times. (On a totally different note, I wonder how many readers I’d have by now if I’d started writing under the name of Harvey Wallbanger? Maybe I don’t want to know the answer.)
To be honest, I’ve always had a bit of a nervous feeling about anyone in the sciences who really seems to enjoy pop business books. Most of the big sellers seem to be full of post hoc reasoning, sweeping statements that are backed up by weak or nonexistent evidence, and plenty of blatant padding. (Other than that, I like ‘em just fine, I guess). I think that a good scientist should always be asking “Hmm. . .I wonder if that’s true?” about every assertion, particularly when someone’s trying to sell you something or claims to be imparting some vital information. And it’s hard for me to reconcile that worldview with this sort of stuff:
(Gary) Hamel specializes in identifying a handful of currently sexy companies, drawing hasty conclusions about the reasons for their success, and then writing books with advice like "go non-linear," "listen to the periphery," and make your company "an opportunity-seeking missile." Later, when some of those companies fail, see their executives carted off to jail, or both, it's no skin off Hamel's back, because he's already penning his next breathless tome.
It's good work if you can get it, I suppose, though not perhaps if you care about where your soul goes after you die. (And if Dante was right about hell holding particular punishments for particular fiends, then there's a whole mess of Harvard Business Press authors who are likely to find themselves sitting on uncomfortable metal chairs for an eternity-long PowerPoint presentation on The New Economy 2.0.)
Now, I like that idea. In fact, I like it so much that I’m going to do something that I’ll probably regret: nominations are open in the comments for new slots in a Dante-style Inferno for various scientific and pharmaceutical sinners. At the moment, I’m picturing the Circle of the Clueless, wandering around for eternity trying to find their rear ends with both hands, but I’ll let the readership take it from there. . .
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Well, so much for that "no deadline" statement from Roche the other day. It turns out that the tender offer for Genentech shares expires on March 12 - and if you want to read the whole thing, you can find it here. That link is thanks to the Wall Street Journal's Health Blog, where it's pointed out that the two companies seem to be disagreeing over Genentech's value (no surprise!) and on the financial assumptions that have been made along the way.
Genentech says that they'll make a recommendation within a few days - odds are that they'll tell their shareholders to sit tight, and in that case, the race is on. Will Roche raise their offer? The market certainly thinks so, with DNA closing yesterday below 83. . .
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February 9, 2009
Viropharma has announced that their Phase III trial of maribavir, a compound targeting cytomegalovirus, failed big-time. Well, they didn't used the term "big-time", but they might as well have. The treatment group (patients with recent bone marrow transplants) showed no difference in CMV infection rates compared to placebo. This is especially disappointing, considering that the compound looked pretty good in Phase II. That's a useful lesson in the difference between Phase II and the real world.
The company has been through this before. Back in the late 1990s, they were working on another antiviral, Pleconaril, that in those heady days caused their stock to shoot up well over $50/share. Some people had gotten it into their heads that the stuff was going to cure the common cold and who knows what else besides. In the spring of 2000, the bad news came in that the drug would do nothing of the kind. I was short the stock at that point, and I've long wished that I had a videotape of me trying to call my broker after I saw the stock quote that morning. I kept missing the buttons on the phone; it was pretty entertaining.
Maribavir isn't one of VPHM's own creations, actually - they licensed it from GSK, and it's a good ol' nucleoside analog in the tradition of many antivirals. But that's a tough area to work in, and today's bad news is just more proof.
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And here’s an even more Macro topic: when do you think the new administration is going to turn its attention to the drug industry? That’ll be after this stimulus-bill business is settled, one way or another – and the only thing I’ll say about that, this not being the soapbox for my political opinions, is that (as far as I know) the only way for the government to come up with money to spend like this is to tax it out of its citizens, borrow it from third parties, or print it from thin air.
But once we’ve decided which of those will bring us prosperity, health care will surely make its way up the list, even if Tom Daschle won’t be around to lead the effort. So I’m throwing this question out to the readership: what are we in the industry likely to see, and to what effect? Negotiation of Medicare drug prices? Reimportation or other attempts to arbitrage the difference between US prescription prices and those in many other countries? And how about the FDA – without a new commissioner, it’s hard to say what the administration’s up to, but who do you think we’ll see? (Here are the current front runners).
Speculate away in the comments; later we’ll see whose crystal ball has been properly shimmed up.
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So, here’s a question for you: just how long is Roche going to keep their offer open for Genentech? They left their friendly-in-retrospect offer on the table for quite a while, until it was clear that nothing was going to happen. So how long are they prepared to wait? They say that there's no set date, which is a bit odd.
These tender offers generally have some sort of deadline on them, to spur shareholders into action. People have to sit down and think about it: well, is this a fair deal or not? Should I take the offer, turn it down, hold out for a better price as the deadline gets closer? And there’s also the moving-target problem. Stock prices are nothing if not fluid (“The market, sir, will fluctuate!” as J. P. Morgan put it), and that $86.50 price may well look a bit silly (in either direction) after it’s hung out there on the clothesline for a few weeks.
And the longer things go, the more expensive a deal could be. As the Wall Street Journal points out, Roche could end up issuing bonds to pay for a deal that it hasn't even done yet. What happened to those careful, cautious Swiss?
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February 6, 2009
AstraZeneca's CEO bets on China, and says that company isn't in the market or a big merger or acquisition. (The same comments that came up when GSK said this the other day can be assumed to have been made, if readers want to save time. . .)
Carl Icahn is making another run at Biogen, nominating his own candidates for the company's board of directors. This will doubtless be an ongoing soap opera for some time.
From another board of directors' meeting, a change at the top at Vertex.
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I did something in the lab the other day that I hadn’t done in several years: run some preparative TLC plates. I had some small reactions that needed to be cleaned up, and the HPLC systems were all in use, so I thought “Why not?” (I wrote here about the decline of analytical TLC in general in some labs, and I think it's fair to say that the larger-scale prep version has seen an even steeper drop in use over the years).
Prep TLC, for those of you not in the business, is a pretty simple technique. You take a square glass plate that’s been coated with a dry layer of ground silica, a white slurry that for this application is about the grittiness of flour or ground sugar. You then take your mixture of gunk, dissolve it up in a small volume of solvent, and deposit it in a line across the bottom of the plate, an inch or so up from one side and parallel to it. Then you take a large glass container and add some solvent to the bottom of it, and put your plate in so that the streaked line of material is near the bottom. Here's one running.
The solvent soaks into the layer of silica, and after it gets up an inch or so it hits your line of stuff. As it continues to move up, soaking further and further up the glass plate, the different components of the mixture will be carried along at different rates. The compounds that stick to silica gel (for one reason or another) will lag behind, while the ones that don’t will move out into the lead. After an hour or so, the solvent line will be up near the top of the plate, and your mixture will now be spread out across it into a series of bands. (The TLC page at Wikipedia has some useful images of this). Up at the top, running with the solvent, will the the nonpolar stuff that didn’t have anything to slow it down. Right down near the bottom, not far up from your original streak, will be the most polar stuff, especially any basic amines – silica gel is mildly acidic, so the amines will stick to it very tightly indeed. And in between will be the other components, divided out according to how they balanced out the pull of the silica gel support with the attraction of the solvent moving them along. Sometimes you can see them as colored bands on the silica plate, but more often you shine a UV light on the whole plate to see them. The silica we use has an ingredient that makes it fluoresce green under ultraviolet, and our compounds usually show up as dark blue or purple bands against the green. It’s a color combination known to every working synthetic organic chemist.
You can see that picking different solvents for this process can change things a great deal. A weak solvent (like hexane) will allow almost everything to stick to the silica. (A compound has to be mighty greasy to be swept along by just hexane; I doubt if there’s a drug in the business that you’d be able to clean up that way). A standard mix is some proportion of ethyl acetate mixed with hexane. You can go up to straight ethyl acetate, or even further by mixing in methanol or the like. And if you’re desperate, you can go to most any solvent mixture you like – three-solvent brews, toluene, acetonitrile, acetone, whatever works.
So how do you get the things off? By the lowest-tech method you can imagine. You mark the position of the band (or bands) you want, and then take a metal spatula and scrape the silica there off the plate. You them dump that into a flask and stir it with a strong solvent, then filter off the silica and wash it some more to rinse your compound out.
This used to be much more of an everyday technique, but automated column chromatography (same principle, pumped through a tube) has taken over. But prep TLC still has its appeal. Done with skill, it can provide very clean compounds, with quite good recovery. In fact, its low cost and power have made it a favorite technique at places like WuXi, the outsourcing powerhouse in China. I've had several first-hand descriptions of their prep TLC room, with rows of plates being run, marked, and scraped in assembly-line fashion. It's the sort of thing you'd only do in a cheap-labor market, because of the unavoidable hand work involved, but it is effective.
I don't know where WuXi gets its plates, but if you make your own, it's an even cheaper technique (discounting labor costs, naturally). You take up the silica gel powder in water, make a thick, well-mixed slurry out of it, and spread it across a square of glass, shaking and tapping it to get the air bubbles out. Back when I was doing summer undergraduate work, I poured a number of these things, although it's certainly nothing I've had experience with since the first Reagan administration. For all I know, that's how WuXi does it now. Perhaps they've found a low-cost supplier of their own, but the idea of a cheap supplier for a Chinese outsourcing company is an interesting one all by itself. . .
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February 5, 2009
GlaxoSmithKline says that they're going to cut yet more staff - this follows up on those reports in the UK press the other day. Interestingly, they're also declining to give any guidance on their 2009 earnings. (Personally, I'd be just as happy if everyone declined to give guidance at all times, but I realize that this would affect the capital markets a bit). And, to the company's credit, they say that they're not in the market for a big merger. Their CEO told the press that "There is no way we are going to be distracted by large-scale M&A within the pharmaceutical sector -- that's not for GlaxoSmithKline."
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Today I can recommend this interview with Sir James Black, discoverer of propranolol, cimetidine, and more. He's 83 and has a lot to say about the current state of the drug industry:
He becomes agitated when discussing a Harvard Business Review article from 2008 by Jean-Pierre Garnier, the former chief executive of GlaxoSmithKline, on the future of drug development. He agrees with the prognosis, but is fundamentally at odds over the prescription for change. . . He has no time for classic industry clichés such as "blockbuster" medicines; no truck with the modern approach to peer review; and no patience with any re-writing of history to suggest a more complex contemporary era of drug discovery has replaced one of "lowhanging fruit" in the past. . .He raises his eyes skywards when he discusses last week's $68bn (£48bn) takeover by Pfizer, the world's largest pharmaceutical group, of Wyeth, and says the restructuring to come will sap both teams. "Will they never learn? They will completely exhaust each others' energies for two years."
A lot of people sent that Gautier article along to me, and I meant to blog about it all last fall, but I just couldn't put myself into its worldview enough to do it. And all the talk about Sanofi-Aventis looking to get bigger, Merck saying that they can't rule anything out (Merck! Doing a big merger? Say it isn't true. . .) Well, let's just say that this doesn't look like the kind of future I really want to experience.
So Sir James's viewpoint is refereshing, in a way. He goes on to talk about the general uselessness of marketing forecasts, why you shouldn't let yourself be pulled out of R&D into bureaucratic shuffling, and many other useful things. Read the whole thing, as the blogging phrase goes. . .
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
February 4, 2009
I see that there’s a new biochemistry building at Oxford, written up here in Nature. It was designed by a London architectural firm, Hawkins\Brown (love that backslash, guys, so very modern of you), and according to the article, the design:
”. . .ensures that the 300 researchers working there communicate as much as possible. The traditional layout is reversed: here, labs are on the outside, divided by clear glass walls from the write-up areas, which are open to a vast, five-storey atrium. Everyone is visible. Open staircases clad in warm wood fly across the atrium at odd angles, and each floor hosts a cluster of inviting squashy leather chairs and coffee tables, giving the impression of an upmarket hotel.”
You can judge for yourself here. But as I was reading that, I kept wondering, where have I heard descriptions like this before? Oh yeah, the last time I moved into a new building. Actually, every single time I’ve moved into one, come to think of it. I was part of a gigantic corporate move in 1992 into what was billed as a “high-interaction facility”, which was nothing of the sort. And then at the Wonder Drug Factory, one of the new lab buildings had the whole research area behind a large glass wall; it was the first thing you saw when you came into the place. Unfortunately, since it was full of snazzy equipment, it became part of the standard tour for visitors (the combichem labs were largely abandoned by then), and the people working there sometimes felt like zoo animals. And my current building has the labs all around the outside walls, and a huge atrium in the middle of the building (to what purpose, no one is sure; it’s completely empty).
Most of the Nature article, though, is taken up with the artworks that were commissioned for the new building. I can’t pronounce on these without seeing them all, although the hanging birds display reminds me of a display I saw hanging in a shopping mall in St. Louis in the late 1980s. I do get a bit worried when I hear some artwork described as “rais(ing) questions about how we organize and view the world around us”, since that’s the worst kind of boilerplate artspeak. (Find a large abstract installation you can’t use it on). Another statement about how “if you have a greater degree of visual literacy, you reflect more on both the way you represent things, and also the way that may limit the way you think about them”, falls into the same vaguely depressing category.
“Time will tell if money spent on art gives a significant return in scientific discovery”, is how the article ends up. But how will we know? Set up a control building with no artwork at all, or one furnished only with the Pre-Raphelites? (Full disclosure – I’d rather work in that last one). My guess is that the people who work there everyday will gradually stop seeing the artworks at all; their biggest effect will be on visitors, for what that’s worth.
And as for laboratory building design in general, my suspicion is that there aren’t that many useful general design schemes. Once you’ve fallen into one of those slots, what will matter most for productivity will be the boring details about the size of the benches and hoods, the ease of using shelves and cabinets, the number and location of electrical outlets and sinks, and so on. As for interaction between the scientists, I agree that it does a lot of good: but how to force it? There seems to me to be a tradeoff between convenience and interaction – the most interactive buildings I’ve worked in were the ones that forced me, though a limited number of doors and stairs, to walk down long corridors past a lot of open (and rather cramped) offices and labs. Spread things out, put in a lot of access points, and people just won’t see each other as much.
So here’s the question: I’m sure that many of them can hurt it, but has anyone worked in a building that seemed to help discovery? Examples welcome, and feel free to link to pictures.
+ TrackBacks (0) | Category: Life in the Drug Labs
February 3, 2009
Nature is rightfully drawing attention to the case of Arash and Kamiar Alaei, physicians (and brothers) from Iran, who have been sentenced to years in prison for supposedly "communicating with an enemy government". Their real crime seems to have been attending international conferences, talking about HIV as a public health problem in Iran, and doing so alongside representatives of US-based groups.
As the journal points out in an open letter, Mahmoud Ahmadinejad has been traveling around telling everyone about how wonderful scientific collaboration is. Watch their hands, not their lips, though. My sympathies go out to the Alaei brothers, along my hopes that international pressure might secure their release or make their appeals successful.
And my sympathies also go out to those scientists and physicians in Iran who have to work under such conditions - as the record of many expatriates shows, Iranians excel in such work when fools are not clapping handcuffs on them.
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Organic chemists, my tribe, have accomplished a lot. But we’ve managed to convince people that we’ve accomplished even more than we have. The general assumption seems to be that we can pretty much make anything, given enough effort. Considering some of the awful molecules that have been made, I can see where that opinion comes from – mind you, as has been discussed around here, many of the toughest molecules have been made by terrible human-wave tactics and unscalable grad school conditions. But they have been made.
So, given unlimited time and money (and cruelty), I suppose it’s true that we can make most anything. But, as many spoilsports keep pointing out, these hideous natural product molecules that take us so long are also being made under much more impressive conditions. But not by us. That hit me when I was in graduate school myself, working on a macrolide antibiotic structure. Reading up on the stuff, I found that it had been isolated by culturing a bacterium from a soil sample taken from a Texas golf course. I got to thinking about that. Here I was, slaving away nights, days, weekends and holidays to get within hailing distance of the structure, and this prokaryote was sitting around in the dirt of the fourteenth green, listening to golfers curse while making my molecule at ambient temperature, in water, and at the same time doing everything else it needed to do to stay alive. Worth thinking about, it was.
I realized then what others had already been saying: that our best synthetic methods really didn’t stand up to what enzyme systems were capable of. Years of medicinal chemistry have done nothing to alter that opinion. Everyone in this line of work has seen what the liver enzymes can do to our carefully constructed molecules, reaching in and oxidizing them to make them sluice out in the urine more quickly. And those transformations are things that, for the most part, we just can’t do. Can you pick up a complex molecule and selectively put a para-hydroxyl on just one of its aryl rings? Nope, me neither. Can you make an epoxide out of benzene (without tearing everything else to shreds?) I doubt it; I sure can’t.
No, the more you know about chemistry, the more humble you feel when you look at enzymes. There’s no substitute for holding down the molecule and working on one part of it with hammer and tongs – it’s a totally different world than the bulk solution-phase stuff that we do in our reaction vessels. Enzymes are the original nanotechnology. They give us something to aspire to.
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February 2, 2009
The market definitely does not seem to think that Roche's offer for Genentech is going to go through at $86.50. Check out the stock action - note the immediate drop on the announcement of the offer, and the less-than-impressive recovery today. Everyone's waiting on new Avastin data, which (if strong) might allow Genentech to tell Roche to go away - or, at least, come up with a much higher offer, which in the current climate is the next best thing.
The Financial Times says that Sanofi-Aventis is looking to do a big acquisition of their own, not content, it seems, to watch Pfizer go down the chute alone. Thanks to the WSJ Health Blog for catching this one. More as we learn more, and I can't imagine that we're going to like what we hear - although, to be sure, they have managed to leave more research sites open, on the whole.
And GSK seems ready to announce more job cuts, but the UK papers seem to have this happening more in that country than anywhere else. No official word from the company, but it's definitely plausible.
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Several readers pointed out the comments of Paul Stoffels, head of R&D at Johnson & Johnson, as reported in the Wall Street Journal’s Health Blog. He’s boosting some sort of open-pharma research model, although what he means by that isn’t too clear:
“All simple diseases have been solved,” Stoffels said. “The next-generation drugs, therapies, are much more complex… You need much more information and science than what you can get out of your own internal labs.” . . . The future of the drug industry, Stoffels told the Health Blog, is “building networks where together with a number of different groups you come up with solutions to solve different medical needs.”
There are a couple of things worth noting in there. The comment about all simple diseases having been solved, for example – people in the industry make that point (I’ve made it myself), but is it true? Forced to choose, I’d say that it’s more true than not, but I’d also point out that even the “simple” diseases aren’t so simple, in retrospect, and that we should think hard before we start trying to put together any list of diseases we’ve “solved”. I’m trying hard to think of some right now, and I have to say, the list slows down once you get past polio and smallpox. We’ve been able to improve a lot of bad situations, but “solved” is a strong word. Blood pressure? Heart disease? Definitely helped, helped a great deal, but “solved”? I don’t think, for example, that insulin solves Type I diabetes.
As for the network thing, this doesn’t seem that revolutionary to me. Drug companies have been bringing in all sorts of collaborators to help out with development. The fallacy in this is, though, thinking that the information you need to make a great drug is always out there. To me, that’s one of the hardest parts about drug discovery: the way that some of the most important factors are still black boxes. What “different groups” can you bring in that will predict that failure in two-year rodent tox, which hits you in Phase III? That said, one important benefit of getting different eyes onto a project is to break up group thinking, and that goes for every stage of a project. Those things that Everybody Knows can really come back to bite you – in advanced stages, you get things like Pfizer’s billion-dollar forecast for their inhaled insulin disaster, Exubera.
The comments to the post make the usual analogies to open-source software development. That breaks down, though, when you consider that the resources needed to write code are a lot easier to distribute than the resources needed to discover drugs. NMR machines, animal labs, and compound repositories are a lot harder to scatter through a thousand basements. . .
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