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
October 30, 2006
Here's my latest contender for an award in the highly competitive Desperate Press Releases category: Albany Molecular says that it has an anticancer compound. Well, it has one that's going to move into "advanced preclinical testing", and if everything goes perfectly, they'll try to submit an IND by the end of 2007. Which means that the first bit of Phase I testing, the toe-in-the-water look at blood levels, can be realistically expected no sooner than sometime in 2008.
The headline is "Albany Molecular to Test Cancer Compound", which the unwary might suppose means that they're going to test it against, well, human cancer. But who knows when that might happen, because I read the press release to mean that the compound hasn't even gone through real small-animal toxicity testing. Is that a long way from human cancer patients? Is Auckland a long way from Albany?
Now, I understand that AMRI hasn't been down this road too many times before. Looking at this chart, it appears that this project is the most advanced they have, and I don't recall them ever heading for the clinic before. That's because the company has been mainly an outsourcing venture, a place to get compounds and libraries made for you. With that business model under pressure, they've decided to give in to temptation and become a drug company.
It's not an easy living, and they're just getting started at it. The programs they have listed are all at the seedling stage, just barely edging into reality by the standards of people who've seen things crash in Phase III. There are probably plenty of people at AMRI who feel the same way, actually - I know that they have a number of scientists and managers who've worked at other drug companies over the years. They know the score, even if their PR department doesn't.
The compound being trumpeted today is said to be a tubulin inhibitor, which puts it in the same class as the taxanes. That's an interesting cancer target, and it's not always easy to get good chemical matter against it. Still, there have been a lot of compounds reported over the years, many of which have never been heard from again. Here's a recent review (PDF, which may be subscriber-only) on the compounds that are already in the clinic. It's a tough area, and not exactly an uncrowded one.
But really, good luck, guys. I hope the compound makes it through the mice, and the rats, and the dogs, and histopathology and formulation and GMP scale-up and all the rest of the whirlpools. Just try not to press-release the world every step of the way, OK?
+ TrackBacks (0) | Category: Business and Markets | Cancer
October 29, 2006
In his book The Periodic Table, Primo Levi mentioned in passing that "chlorides are rabble". That struck me as very well put, and is proof enough (should anyone need one) that Levi had a real feeling for his chemistry. The reason that comes off so well is that when you look through a chemical catalog, if there's only one salt of a given element available, it's almost always the chloride. They're common, in every sense of the word.
The kinship of the positive ions, the elements themselves, are well known. That's how Mendeleev worked out the periodic table, and generations of chemistry students are taught about the similarities among its columns. It's all true, of course, but there are subtle kinships of the counterions, too, a faint Y axis to the strong X of the elements.
Most of the chlorides are quite boring - white powders, almost invariably. The more chromatic elements still manage to do something for you: nickel chloride, for example, is a vivid green (copper less so), and chromium (III) chloride is a striking metallic-flake purple. But if you can't get colorful with elements like those, your counterion is a total loss, anyway.
Fluorides are almost never colorful, but they have a tough nature about them, reflecting their ultimate-hard-anion character. Iodides are the other end of the scale - that's such a big, fluffy ion that it hardly seems bound at all sometimes. Even light is enough to mess with it, and it's a rare iodide that doesn't have a warning on its label to keep it out of the sun, for fear of it turning brown in a death-tan of oxidation to free iodine.
Sulfates are nearly as boring as chlorides, but with a bit more character to them. Nitrates (similar salts from a strong acid) have a much different feel to them, since when you're working with them you can never quite get the thought of explosions out of your mind. It's not completely accurate, but it's still true that you could mix potassium sulfate with sulfur and charcoal forever and never discover gunpowder. The word "nitrate" itself has a menacing sound that it'll never lose.
If you want real problems, though you have to turn to even more loosely bound, oxygen-rich things like bromates, iodates, and (above all) perchlorates.
That's about as bad as it gets inside the confines of inorganic chemistry - to get crazier, you have to trespass into organicky things like azides. Most of the organic counterions, though, are carboxylate salts, which are relentlessly similar to each other. No explosions here - if there's one salt of a element that's guaranteed to be more yawn-inducing than its chloride, it must be the acetate.
These are all classical ions, known for centuries. The fluorides are probably the most nouveau of the lot, since even though some of them occur naturally, most of them had to wait until the industrial development of the element later on in the 19th century. But that led in the 20th to all sorts of odd creatures that (so far as I know) are never found in natural minerals at all. The higher fluorides, things like tetrafluroborate and hexafluorophosphate, have only human fingerprints on them. When you work with those salts, you've thrown your lot in with the synthetic, the man-made, the new and improved. Even weirder ones are surely on the way.
+ TrackBacks (0) | Category: Life in the Drug Labs
October 26, 2006
The late-stage clinical failure of a small company/big company drug partnership story gets told over and over, and today it was the turn of Renovis and AstraZeneca. Renovis had come up with a candidate (NXY-059) for post-stroke therapy that targeted free-radical oxidative damage. Initial clinical trials were fairly positive, but this latest one, a larger and more rigorous effort, totally failed to demonstrate any benefits for the drug.
They've got plenty of company. I've lost count of the number of neuroprotective drug candidate failures I've heard about during my time in industry. It's humbling, like much of drug discovery is when you look at it closely. I mean, if you get your information from the newspapers or (God help you) television news segments, you'd think that we know just how tissues are damaged after an event like a stroke, which means we know just how to block the process, so all it takes it just sending in some drug to keep it from happening. The folks in the lab coats should be whipping one right out any day now.
Nope. Hasn't worked out. Excitatory glutamate toxicity for example, was all the rage about ten years ago, but a number of Phase II and III wipeouts showed that even if these drugs could work (a big if), they would have to be given very, very quickly, which isn't clinically realistic. Since that run of failures, a new set of standards were developed to try to improve the quality of clinical candidates and trials in the field. The Renovis drug is one of the first to come in under those criteria, but little good did they do in this case. Neuroprotection is hard.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Central Nervous System
October 25, 2006
There's an interesting analytical chemistry paper in the preprint section of PNAS (open access if you want to read it) that may reopen an old controversy. It's from a large multinational team (Mexico, Spain, France, NASA-Ames) investigating the GC-mass spec instrumentation that was flown to Mars on the Viking landers in 1976. That's a key instrument in the life-on-Mars debate, so an attack on it is significant. First, though, some background - it's a tangled story.
The Viking landers each had three biology experiments to look for possible signs of Martian life, whose results were famously difficult to interpret. They produced both excitement and confusion at the time (scroll down in that NASA history page) and they've been fuel for arguments ever since.
There was the pyrolytic release experiment, which incubated Martian soil with 14C-labled carbon monoxide and carbon dioxide. After several days, the sample was purged, then heated to 650C and analyzed for the release of any labeled carbon compounds that might have been formed by living organisms. A control sample was heated before incubation, to kill off any such life forms. Seven out of the nine runs of this experiment seemed to produce positive results - that is, volatile labeled carbon was produced after pyrolysis.
The gas-exchange experiment used the same sort of apparatus, exposing the soil to either water vapor or nutrient solution under a mixed atmosphere of gases. The headspace was analyzed for changes in the concentrations of the various components, which could be due to biological uptake or release. This one showed a strong release of oxygen and carbon dioxide from the samples once moisture was added, but the amount decreased over time, leading to theories that this was the product of an inorganic reaction rather than a signature of life.
The labeled release experiment put Martian soil into a dilute nutrient broth, with several small organic compounds which were all labeled with 14C. After incubation, the headspace of the experimental cell was analyzed for any released labeled gases and again, a control experiment was done with pre-heated soil. This one produced exciting data, with release of labeled gas in the experimental samples well over those in the controls. One odd result, though, was that the subsequent injection(s) of nutrient solution did not produce a further spike of released gas. The final curves ended up looking neither like what you'd have expected from a classic bacterial positive, nor from a simple chemical reaction. This ambiguity has meant that the LR results have been re-analyzed and re-fought ever since the 1970s, with the experiment's designer, Gilbert Levin, leading the effort to rescue the data as a case for Martian life.
But then there were the GC-MS data, from an experiment considered to be the backstop test in case the biology experiments were difficult to interpret. Since they certainly were that, from beginning to end, this experiment became for many people the most important one on the landers. (It already had been for the people - a not insignificant group - who thought from the start that the biology tests were unlikely to provide a conclusive answer). This one heated soil samples directly and looked for volatile organics. Heating to 200C showed little or nothing in the way of carbon compounds, and very little water besides. By contrast, another sample taken up to 500 degrees released a comparative flood of water, but still showed no evidence of organic molecules.
And that, for most observers, was that. No organic molecules, no life. Explanations after the GC-MS results mainly turned to what sorts of inorganic chemistry might have given the behavior seen in the three other experiments. Martian soil was thus hypothesized to be a sterile mixture of interesting chemicals (iron peroxides? carbon suboxide polymers?) that had fooled the biology test packages, but couldn't fool the GC-MS.
There's always been an underground, though, that has held that the results were indeed the result of life. Gilbert Levin has never given up. In 1981, he pointed out that tests of a Viking-style GC-MS instrument had shown that it was insensitive to organics in a particular Antarctic soil sample, but that this same soil nonetheless gave a positive result in the LR experiment. And he really put his opinions out in the store window in 1997, with a paper that flatly concluded that the 1976 LR experiments had indeed detected Martian life.
In the last few years, others have joined the battle. Steven Benner at Florida, whose work I wrote about here, published a PNAS paper in 2000 which maintained that organic molecules on Mars would likely be retained as higher molecular weight carboxylates, which would not have been volatile enough for the Viking GC/MS instrument to detect. And now this latest group has weighed in.
They've also analyzed various Antarctic and temperate desert samples, and found that all of them contain organic matter that cannot be detected by thermal GC-MS analysis. And the ones that contain iron, including the NASA reference simulated Mars soil (a weathered basalt sample from near Mauna Kea), tend to oxidize their organics quickly under heating. The conclusion is that while much of the water and carbon dioxide produced in the Viking experiment from heating the Martian soil was surely inorganic, some of it could have been from the oxidation of organic material. The paper concludes that the Viking GC-MS results are. . .inconclusive, and should not be taken as evidence either way for the presence of organic molecules or life. The question, they feel, is still completely open.
The good news is that future missions are relying on other technologies. In addition to good ol' thermal volatilization/GC-MS, there are also plans for solvent extractions, laser desorption mass spec, short-path sublimation, and other nifty ideas. If these various US and European missions get off the ground (and on the Martian ground), we're going to have some very interesting data to look at. And argue about.
+ TrackBacks (0) | Category: Analytical Chemistry | Life As We (Don't) Know It
October 24, 2006
Man, are there ever a lot of companies that I've never heard of on that compound code list. Looking over the names, some of which are clearly more inspired than others, I'd like to suggest a few biotech naming rules. Some of these I know have been previously proposed, both in our field and in other tech areas, but those gentle suggestions do not seem to have sunk in. So. . .
1. Enough of the letter X already. Ending your company name with it puts you in the middle of a herd, starting with it makes you look desperate, and putting in the middle doesn't do you any good. Double x? Idiotic. X out the x, please. It isn't high-tech any more: doesn't anyone realize that Xerox itself started using that name more than forty years ago? And at least they had a derivation from a real word on their side, not something that sounds like a space cat coughing up a hyperspace hairball.
2. Enough of the damned InterCaps, while we're at it. This was an awful fad twenty years ago in the software business, and for some reason it doesn't seem to have died out in the biotech/pharma world. No one wants to reach for the shift key in the middle of your company's name, and no, it does not look spiffy. It makes you look like a shareware company developing hot new apps for Mac OS 7.
3. Putting your company's name in lowercase is an even more pathetic attention-seeking device. Everyone who types your company's name will roll their eyes, and half the time they'll capitalize it out of inattention or sheer spite. And as for starting in lower-case and switching to all caps, words fail me. I'm looking at you, deCODE. deSIST!
4. Naming your company after the disease, body part, or function that you want to work on is fine, if rather unimaginative. But naming it after the way you want to do it sounds a bit. . .boastful. Calling yourself "Predictomatic Pharmaceuticals" or "IntelliDesign Biosystems" sticks you right into the "put up or shut up" category. And yes, it's true that this is the category that all small companies are in, when you get down to it, but you don't necessarily want to be so blatant about it.
5. The following words and word fragments should be deleted from all further lists of possible biotech names: Ribo. Thera. Immuno. Gen(e). Med. Tronics. Vax. Bio. Anti. I realize that this may well leave some of you with no possible names at all. Take that as a sign.
+ TrackBacks (0) | Category: Drug Industry History
October 23, 2006
Drug candidates go by many different names during their lifetimes. At first, they're known to the chemists on the project by tags like "Jane's analog" or "the one with the methyl group". As time goes on, though, they tend to be known more by their official compound number. Every drug company has some sort of system for this; in almost all cases it's a letter-number combination that identifies the company and the compound. But there's no standard. You're free to assign different letters to different therapeutic areas or research sites if that sounds good, or dole out different blocks of numbers for different purposes instead of running them in sequence.
Biologists, in my experience, tend to use these numbers earlier in the course of a research project than the chemists do. That's surely because we have more of a structural handle to remember the compounds by ("that piperazine with the chiral isopropyl coming off it"). This leads to scenes in project meetings where the biologists ask if there's any more 5650, and the chemists look blank, and then the chemists ask if there's any data on the homopiperidine, and the biologists look blank. Likely as not, they're talking about the same compound.
A quick look around Google didn't turn up any guide to the various compound codes in use, so I thought I'd provide one. (No doubt this post will start a small, steady Google-search tap dripping in my traffic statistics). Some of these represent companies that are no longer with us under those names, but the codes live on in development candidates, literature compounds, and catalog reagents. I've tried in include later merger/buyout partners in parentheses. This is a fairly comprehensive list (do you know anyone who can name all the drug companies in Japan? Me neither), but I'd be glad to add others as suggested - I'm sure that there are plenty of smaller companies I've left out.
A small "x" represents a variable letter - Novartis, in particular, seems to have appropriated great swaths of the alphabet for its internal use, although I think that some of their compounds get renumbered when they're ready for the spotlight. So, here goes:
AG Agouron (Pfizer)
AVE (Sanofi) Aventis
BIxx Boehringer Ingleheim
BMS Bristol-Meyers Squibb
C Carbogen (Ubichem)
CKD Chong Kun Dang
DRF Dr. Reddy's
EMR Merck KgaA
F Pierre Fabre
HMR Hoechst/Marion/Roussel (Aventis)
IC Icos (Lilly)
JNJ Johnson & Johnson
JTx Japan Tobacco
KB Karo Bio
MK Merck (in development)
NN Novo Nordisk
NSC Nippon Shinyaku
PD Parke-Davis (Pfizer)
PHA Pharmacia (Pfizer)
RGH Gedeon Richter
RWJ Johnson & Johnson
SGN Seattle Genetics
SU Sugen (Pfizer)
T Tularik (Amgen)
V Purdue Pharma
YKP S-K Biopharmaceuticals
ZK Schering AG
+ TrackBacks (0) | Category: Drug Development | Drug Industry History
October 22, 2006
"You like those scatterplots, don't you?", someone said to me the other day. And I can't deny it. On most projects that my lab has been assigned to, at some point I end up messing around with all the project data, plotting one thing against another and looking for correlations.
Often what I find is negative. Plotting liver microsome stability (a measure, in theory, of one of the major pathways for drug metabolism) against compound blood levels in animal dosing has rarely, in my perhaps unrepresentative experience, shown much of a correlation. In vivo blood levels are just too complicated, and influenced by too many other things. But I'm often surprised by how many people assume that there's a correlation - because, to a first approximation, it sort of makes sense that there might be - without actually having run the numbers.
That's a theme that keeps recurring: a fair amount of what people think they know about their project isn't true. I think it's because we keep reaching for simple explanations and rules of thumb, in hopes that we can get some sort of grip on the data. We give these too much weight, though, especially if we don't examine them every so often to see if they're still holding up (or if they ever did in the first place).
Another factor is good ol' fear. It's unnerving to face up to the fact that you don't know why your compounds are behaving the way that they are, and that you don't know what to do about it. It's no fun to plot your primary assay data against your secondary data and see a dropped-paintcan scatter instead of a correlation, because that kind of thing can set your whole project back months (or kill it altogether). One of the biggest problems in an information-driven field is that not everyone wants to know.
One time when I was giving the numbers a complete run-through, I noticed one of the plots actually seemed to have a fairly good shape to it. Y-axis was potency (plotted as -log), and there it was, actually increasing - broadly, messily, but undeniably - with the X-axis, which was. . .corporate compound number, the one assigned to each new compound as it was sent in for the assay. Oh, well. It showed that we were making progress, anyway. And at least nobody suggested that we attempt to give the compounds numbers from years in the future, in order to make them instant surefire winners. I've heard sillier suggestions.
+ TrackBacks (0) | Category: Drug Assays | Drug Development
October 19, 2006
Three days before: go to the local supermarket and ask to buy a case of corn starch. Ignore the puzzled looks, which come your way since you don't look like you own a Chinese restaurant. Pay for the stuff out of your own pocket (this is grad school, y'know) and head back to the lab. Ignore the puzzled looks of colleagues who haven't seen you walking around with boxes of corn starch before.
Two days before: mix up a kilo or two of the starch with some dilute acetic acid into a weirdly dilatant fluid. Hold on to the memory of it, unknowingly, for fifteen years or so until you have kids of nursery school age. In the meantime, pour the stuff into a cheap baking pan and put it into a drying oven that no one, since you started in on it, will use for anything else.
One day before: take the baking pan out of the oven, wheezing into the waiting faceful of acetic acid fumes if you try to rush the process. Break the cracked, slightly shrunken white cake into chunks small enough to be loaded into your apparatus. Wonder to yourself if this is how other famous scientists started during their doctoral work, and if it is, how come you never read about it.
Day of prep: load up the reactor, a metal box with a glass tube and ball joint poking out of it, with the chunklets of corn starch. Hook up to a connecting adaptor, with a vacuum take-off on it, which you're going to need, big-time, and a large round-bottom flask at the bottom, ditto. Pour plenty of liquid nitrogen into the dual traps on the vacuum pump, regretting the day that you ever told your summer undergrad, who isn't around, of the potential dangers of LN2 traps, because now he won't get near one.
Hook up the vacuum line and pump down the system, and break out a Fisher burner, without realizing (naturally enough) that you won't use one again for at least twenty years. (Not using corn starch as a starting synthetic reagent for at least twenty years, on the other hand, is something you actively yearn for). Take a deep breath and begin flaming the bottom of the metal box with the burner, making sure to get the whole surface and not to linger too long on any one spot. Moderation, moderation in all things.
Note the wisps of vapor flashing through the glass part of the apparatus, accompanied by a throatier note from the vacuum pump. As the heating continues, look for the appearance of an ever-darker flow of thick heterogeneous syrup. This sticky ooze with black flecks in it is your desired product, damn it all. Continue heating until the lava flow dwindles and its color becomes darker than you think you can ever lighten.
Cool down the apparatus, bleed in some air, pull the vacuum line and kill the pump - in that order, unless you really want to suck oil back into the traps, and you really don't. Now would be a good time to lift those traps out of their liquid nitrogen Dewars, to guard against just that oxygen-condensing explosion risk you foolishly warned your undergraduate student about. Make sure that the pump system is open, though, and that the hose is draped into a fume hood, because some of that odd stuff that's condensed in there is probably carbon monoxide and it will be evaporating shortly.
Turn your attention to your product, which has now cooled into a tarry reddish-brown glass. Dissolve it in water and transfer it to the three-foot-tall liquid-liquid extractor, which you will eventually describe to people who will look at you as if you are describing how you used to hunt mammoths. Start heating up a three-liter pot of ethyl acetate, make sure that all the hose fittings to the water condensor are tight (about three times should be enough to relieve your paranoia), and go to what passes, for now, for home. Your product will be ready for the next phase of its purification, which involves the irreversible blackening of a thick column of ion-exchange resin, in just under a week.
After that and all the rest of it (the evaporation, the decolorizing charcoal, the methanol, the crystallization), take a small sample of your product and put it in a glass vial, hanging a paper label around its neck. Pack it and take it with you on your every move over the next twenty years so that you have it, with its now-yellowed label with the faded ink structure on it, as you sit down at your computer.
+ TrackBacks (0) | Category: Graduate School
October 18, 2006
There's a curious paper (subscriber-only link) in the latest Nature that's getting some attention, titled "A linguistic model for the rational design of antimicrobial peptides". For non-subscribers, here's a synopsis of the work from the magazine's news site.
A group at MIT headed by Gregory Stephanopolous has been studying various antimicrobial peptides, which are secreted by all kinds of organisms as antibiotics. Taking the amino acid sequences of several hundred of these and feeding them into a linguistic pattern-analysing program suggested some common features, which they then used to synthesize 42 new unnatural candidates. The hit rate for these was about 50%, which is far, far more than you'd expect if you weren't tuning in to some sort of useful rules.
It's the concept of "peptide grammar" that seems to be the news hook here. But I'm quite puzzled by all the fuss, because looking for homology among protein sequences is one of the basic bioinformatics tools. I have to wonder what the MIT group found with their linguistics program that they wouldn't have found with biology software. What they're doing is good old structure-activity relationship work, the lifeblood of every medicinal chemist. Well, it's perhaps better described as sequence-activity relationships, but sequence is just a code for structure. There's nothing here that any drug company's bioinformatics people wouldn't be able to do for you, as far as I can see.
So why haven't they? Well, despite the article's mention of a potential 50,000 further peptides of this type, the reason is probably because not many people care. After all, we're talking about small peptides here, of the sort that are typically just awful candidates for real-world drugs. And I'm not just babbling theory here - many people have actually tried for many years now to commercialize various antimicrobial peptides and landed flat on their faces.
You won't see a mention of that history in the Nature news story, unfortunately. They do, to their credit, mention (albeit in the fourth paragraph from the end) that peptides are troublesome development candidates. That's where it also says that there are reports that bacteria can become resistant even to these proteins, which prompts me to remind everyone that bacteria can become resistant to everything short of freshly extruded magma. It's in the very last paragraph of the story, though, that Robert Hancock of UBC in Vancouver says just what I was thinking when I started reading:
(Hancock) questions how different the linguistics technique is from other computational methods used to find similarities between protein sequences. "What's new is the catchy title," he says.
+ TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases
October 17, 2006
Merck had their DPP-IV inhibitor for diabetes approved by the FDA today, which is good news for them and for many diabetic patients. I'll defer discussion of the mechanism and the compound for now, though, because what I wanted to mention is how this illustrates Merck's business style.
The first compound of this type that most medicinal chemists heard about was from Novartis. They popped up as early as 1999 with the first of many publications on their compound class, and a lot of corresponding patent activity. Merck, for their part, stayed out of the spotlight. You had to watch the patent databases closely to get an idea of what they were up to, and they didn't really publish anything until 2004. Novartis, naturally, had plenty of motivation to keep up with the news and knew that Merck was in the hunt, but they were still surprised earlier this year when Merck filed for regulatory approval months before anyone thought that they were ready.
In some cases, you can get a reading on what Merck is up to when they break from their usual stealth mode. For example, some years ago they appeared with a big splash in Science, touting a small molecule that could actually affect the autophosphorylation of the insulin receptor. An oral competitor to insulin? The dawn of a new era? Nah - just an interesting failed project. The compound was going nowhere, and the only thing it was good for was to make a big noise in Science. The contrast with academic publication habits is noteworthy.
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
October 16, 2006
Reader Steve C. analyses patents for a living, and he's been taking an interest in the Ariad / Lilly litigation. He was kind enough to send along some analysis that he's been working on (on behalf of some paying clients, as opposed to me). After looking through the court documents, he thinks that Lilly has a very good chance of prevailing, and I thought I'd share some of his reasoning, with his permission. I should disclose (again) that I am short Ariad stock, because I expect them to lose their patent, and that I think that they (and others who attempt to claim such things) deserve to lose.
As is the manner of lawyers everywhere, both sides advance a number of arguments, hoping that one of them will stick. In Lilly's case, they claim (among other things) that the claims of Ariad's patent are invalid because they were obtained through inequitable conduct, and that they include non-statutory subject matter. That last part is the argument that I've been making here over the last few years - that Ariad's patent on regulating NF-kB every way under the sun is an attempt to own a naturally occurring process. But Steve, while agreeing with that in light of the Searle/Rochester COX-2 decision, says that Ariad may have even bigger problems
The inequitable conduct argument is one that I hadn't paid attention to before. Applicants for a patent have a duty of candor - you're supposed to inform the examiner of everything that you know of that has a bearing on your application and claims, whether it helps your case or hurts it. Concealing potentially damaging material is grounds for having your patent revoked or declared unenforceable. Lilly argues that figure 43 of Ariad's '516 patent is labeled as the nucleotide and amino acid sequence of a protein that would reduce NF-kB activity, but that it's actually a partial sequence, short some 56 amino acids. They further claim that this shortened peptide wouldn't work, and (crucially) that Ariad knew all about this, but didn't disclose it. As it turns out, this protein was a key piece of evidence during the (lengthy) examination of Ariad's application at the PTO, so losing it would be trouble.
And that leads to an even bigger problem. During the near-endless Ariad patent prosecution, US law changed to become more like international patent law. The term of a US patent used to be 17 years from date of issue, but since 1995 it's been 20 years from date of filing. Ariad had been working this case for sixteen years (no, that's not a typo), and was grandfathered in under the old law. But if they refiled, everything would have suddenly changed (and their patent would have already expired as of last January!)
Lilly is arguing that Ariad was doing everything they could to hide any problems severe enough to cause a refiling. Specifically, they charge that Ariad hid the problems with figure 43, which were crucial to the validity of their claims. They hammer on the fact that the protein in that figure is more or less the only thing in the whole patent that actually is capable of inhibiting NF-kB - without it, there's no enablement, just a bunch of talk about inhibiting and modulating NF-kB with no way shown of actually ever doing it. Ariad, for their part, claims that the whole thing was unintentional, that the examiner had all the information needed to check the figure, and that the difference was so subtle that even Lilly's expert witness didn't pick up on it.
Steve thinks, though, that this could be a killer issue for the whole bench trial. His view is that Ariad's trying to have it both ways: saying that the examiner had all the information needed makes it sound like it's a serious problem that had been dealt with, but then they claim that it was such a small matter that Lilly's witness didn't notice it. Those two defenses can't be simultaneously valid. The extreme importance of the issue makes Lilly's job easier, since they don't have to show as much intent on Ariad's part.
I have no word on when the judge's decision might be coming, but I'll be watching closely. The research world will be better off, I think, when patents like this are no longer an option or a temptation.
+ TrackBacks (0) | Category: Patents and IP
October 15, 2006
Back when I was a first-year graduate student, I had to do something that I'm not sure that folks today have to worry about: pass a German test. Mind you, it wasn't much of a test - you got a passage from a journal article, and could use a dictionary, and you had a couple of hours. Fast page-flipping would get you through it, which is basically how I did it, since I'd only had one semester of the language as an undergrad (and not much of it took). Little did I know that I'd have a year coming up when I'd have to speak the language in order to eat.
You couldn't substitute another language, either, because German is a uniquely important one in chemistry. A lot of the older physical and inorganic (and a huge amount of the early organic) work was done in Germany, which also produced huge reference works like Beilstein, Gmelin, and Houben-Weyl. But perhaps all the verbs in those sentences should be in the past tense, because both of those references are now appearing in English.
Beilstein switched over with the 5th printed supplement, which appeared only after massive delays which led many scientific libraries to give up on their subscriptions. At one point, the print edition was a good thirty years out of date. Organic grad students had regarded Beilstein with awe back in the 1950s and before, but by the 1980s many of them had never used it. The switch to electronic database searching, which was done in English right from the start, brought them back to relevence. Now libraries are having to remind people that the computer-based service used to be part of a printed handbook.
Houben-Weyl, for its part, switched to English in 1990 or so, but that doesn't seem to have raised its profile in the non-German-speaking world. I recall a Dylan Stiles post where he didn't seem to have heard of the work, for example. The publishers finally caught on to the fact that printed reference works are in trouble, and have moved into the electronic age.
So, here's a question for the grad-student readers: does anyone have to take a German exam any more? The importance of the language in chemistry has been in steady decline for decades, and (if anything) accelerated decline for the last fifteen years. And if you do have to take a test, does anyone at your department still know why?
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October 12, 2006
Taking a hint from one of the comments to the last post, I took at look at a recent article in Chemical Reviews, where some folks at Boehringer Ingleheim did the heavy lifting of figuring out how many chiral and achiral drugs have made it to the marketplace in recent years.
I've taken the liberty of turning two of their categories into a graph, shown below. You can see that the percentage of new drugs that are achiral has indeed been decreasing, while the percentage of single enantiomers has increased. I'd like to have some more recent data to see if 2003 was an anomaly or not, but the trend is surely real. (In case you're wondering, the rest of the launches for any given year fell into the categories of natural product/semisynthetics, which I didn't count, racemates (which have basically dwindled to nothing across this time span) and proteins, antibodies, polysaccharides and such).
And I'd like to clarify my point from yesterday: it's not that I don't work on projects that turn out chiral development candidates. In fact, in recent years I've probably worked on more projects that recommended a chiral final compound than an achiral one. But in the drug discovery phase, I do avoid chiral centers until I can see if they're worth exploring. If they're not, then so much the better, as far as I'm concerned.
Take a piperidine, for example, a structural subunit that's every medicinal chemist's friend. As a commentor noted yesterday, if you stick a piperidine on your molecule, attached through the nitrogen (and who hasn't?), you have several choices if it comes back active. You'll probably start varying the substituents on the piperidine ring, since you can buy a lot of them. The first ones will probably be the 4-substituted series, since they're not chiral.
Now, I'll make and send in 3- and 2-substituted ones as well, but I'll probably use things like racemic 3-methylpiperidine first, just to see if it's any good at all. Note that I'm talking about the first binding assay here - if you're going into cells, tissues, animals, tox assays and all that, you want a single enantiomer. But you're only going to do all those things if the compound binds well in the first place. If it comes back as a fifty-micromolar stinkpot, who cares? Odds are that synthesizing the single enantiomers will not suddenly reveal a nanomolar wonder drug. On the other hand, if the racemic 3-methyl comes back good (or even better than the 4-substituted analog), then it's worth checking the enantiomers, because that means that this part of the molecule is probably seeing the chiral protein up close. (Readers with subscriptions to Bioorganic and Medicinal Chemistry Letters can see for themselves that I have not pulled that example out of thin air).
Unless I've got a lot of manpower or a big keg of starting material with an easy purification at the end, I'm probably not going to start off by making all the enantiomers of those chiral groups just to check them in the first assay. Ars longa, vita brevis, y'know. If they all come back bad, it's clear that you've wasted all your time. And if the chirality matters, the activity is going to be all in one series (most likely), in which case you've only wasted half your time. I don't see the upside.
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October 11, 2006
My mention of hardly ever taking an optical rotation led into the question of what to do about chirality in drug candidates. One commentor mentioning hearing someone from one company making a big deal out of including chiral fragments in their molecules, which seemed to contradict my attitude.
It sure does - but I'm right. Well, on this issue I am, anyway. Chirality can be a great help, but it's often purchased at a great price. It's true that our molecules are interacting with chiral protein binding sites, which should mean that the right optically active compound is probably the best fit you can get. But how long will it take you to get there, and what are you willing to pay?
There are chiral centers and there are chiral centers, of course. The ideal situation is a single chiral carbon that you buy from a cheap source (a naturally occurring amino acid, say) which quickly gets turned into something non-epimerizable. That's not so painful, and if it buys you better activity, then why not? Compare that to the other end of the deal, which might be something that can't be purchased cheaply and requires a from-the-ground-up chiral synthesis. It's either that or a good old fashioned resolution, which means that half your work and money has to be thrown away. Throw in some chances of racemization and you're looking at a real campaign, which you'd better have a good reason to embark on.
Other things being equal, I try to avoid chirality. There are plenty of achiral compounds out there that have earned billions of dollars, after all, so why go looking for trouble? If I add a chiral center, I try to make it something that's available cheaply, not some exotic creature-from-the-chiral-lagoon stuff that goes for a dollar a milligram on the easier enantiomer. There's almost always something else you could be doing rather than going down that path.
Still, I'm pretty sure that the number of chiral drugs (outside of natural products) has been increasing over time, although I'd like to know just how much. I'm not sure that I believe the chart here, for example, and I'd like to split out the cases where someone comes in selling a single enantiomer of a formerly racemic compound. But newer reactions are putting more and more chiral chemical space into the "worth a try" category. So I don't fear handedness in my compounds - but I don't seek it out, either. If that interviewer from Company X really does, well, my achiral compounds and I will just watch from a safe distance.
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October 10, 2006
1. A Soxhlet extractor. It's not that I don't like them, it's just that I haven't had the need for one. We used to use one to wash polar products out of all the gunked-up salts from big lithium aluminum hydride reactions, and I once used one to slowly wash a more soluble impurity out of a powdery mixture of isomers. I think some of my younger colleagues have hardly ever seen one, which I find vaguely depressing.
2. For that matter, a liquid-liquid extractor. I had one of these built for me back in grad school that came up to my waist if I set it up on the floor. A week's worth of ethyl acetate washing did wonders for my crude material, which was about as crude as it's possible to get, since it was obtained by destructive vacuum distillation of corn starch. I'll have to go into that story in detail some time.
3. An infrared spectrometer. Last time I put something into an IR, I swear, it must have been nearly seventeen years ago. It's a perfectly good, perfectly reasonable analytical technique that's just been totally swamped by NMR and LC/mass spec technology. It still does some things very well (like tell you if you have a nitrile or not), bu as far as I can tell, no one cares.
4. A polarimeter. I've narrowly dodged this one over the years, but I think I haven't had to get an optical rotation since about 1996. You want to avoid chiral centers if you're making pharmaceuticals, and if you have chirality, you want to buy it in your starting material. And if you have doubts about your enantiomeric purity, you want to use something like chiral HPLC and not trust the specific rotation. Tiny bits of impurity with huge rotations can totally throw the number off. Stick with techniques where the error terms are linear and don't have exponents in them.
5. Cyclic voltammetry. One of my first projects in grad school bid fair to wander off into physical organic chemistry, at least until we found that the effect we were trying to explain didn't exist in the first place. I tried all kinds of odd techniques to get a handle on the (nonexistent) anomaly, and that included wandering down to the electrochemists in the other hallway. It didn't hurt that the grad student who ran the apparatus was really cute. But cute electrochemists are thin on the ground, in my data set, anyway.
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October 9, 2006
A recent issue of Nature (443, 382, 28 September 2006, subscriber link) carried an intruiging article about Japan's five-year "Protein 3000" project, which is now winding down. Carried out under the auspices of RIKEN, the project was designed to use a large-scale NMR facility to solve the structures of at least 3000 proteins, and along the way advance the understanding of protein folding in solution.
Whether or not it succeeded depends on who you ask, because the answer isn't obvious. The project does seem to be on track to make its numerical goals, but according to the article, many protein-structure people think that a large number of the structures that have been solved are, well, junk - easy, closely-related ones that were put on the list to run up the numbers. While the organizers dispute that, as they certainly would, another problem is that understanding protein folding has turned out to be (you know what's coming) harder than expected. The project was supposed to cover a large swath of a hypothetical 10,000 different folds, but now the real number is thought to be two or three times that. So the best case was that Protein 3000 would have worked out about a third of all possible protein folds, but now they're looking at perhaps 5 to 10% of them.
The Japanese government has a real weakness for big programs like this. I think that Protein 3000 has been one of their biggest forays into that area, but in the past they've announced all sorts of gaudy projects in computation and the like, most of which haven't worked out quite as planned. The "Fifth Generation" project is perhaps the most abject failure of the lot, but at least that one seems to have produced a number of researchers who could do something else. But the Protein 3000 business has some folks worried:
Several researchers have also expressed concern that the factory approach at the NMR facility has deprived young researchers there of the skills necessary to solve more complicated and important scientific riddles. It might have "destroyed the next generation", says one.
(Kurt) Wüthrich, who helped plan the NMR centre in 1998 and was a science adviser in 2000-04, agrees that the facility is a wasted opportunity. "A centre of that size should contribute to methodology, but there has been nothing," he says. "It became a one-man show with 40 NMR machines - there is no knowledge."
Not a good review, considering it comes from a man who knows a bit about the use of NMR to attack protein structure. What I find instructive about such things is that these projects are often just the sort that large government-level granting agencies take it into their heads to fund. Sometimes they work out, but the majority of the time they don't.
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A few miscellaneous notes this morning: I had an e-mail from a reader who asks "Why is Imclone stock worth anything at all?" He was referring to the competition they're now facing from Amgen, and the managerial turmoil that's been going on for months now. For my part, I think that IMCL is worth something, but I sure don't think it's worth $29.44/share, which is where I went short on Friday. (In the future, if I write about them, I'll make note of that fact each time in the interest of disclosure). I realize that this puts me on the other side of the fence from Carl Icahn, a person whose stock-picking judgment I might normally defer to. But in this case, I think I may know more about cancer therapies than Icahn does. We'll find out.
On an unrelated topic, I have a request. Does anyone know of a commercial source for a library of diverse phenyl carbamates? I realize that that's not the usual sort of diversity library - if I were after secondary amines, the offers just wouldn't stop. I can find scattered examples from various suppliers, but if someone had a bunch already collected, it would be a great time-saver. Any ideas?
But finally, though, physics is more on my mind than chemistry this morning. I'm digesting the unpleasant implications of this map, courtesy of the US Geological Survey. . .
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October 5, 2006
Since I was asking the same musical question just the other day, I wanted to refer people to this article by Matthew Herper over at Forbes, who also wants to know: where is Acomplia/rimonabant, anyway?
It's amazed me for months now that Sanofi-Aventis can get away with saying nothing at all about the prospects for their potential biggest-selling drug ever. Back when the first FDA action came, I predicted, with miserable inaccuracy, that the company would have something to say within days. It's been months, and no one knows anything more than we did back in February.
As the Forbes piece makes clear, analysts and institutional investors seem to be losing patience. I'm not sure what it is about the Sanofi corporate culture that makes this strategy seem like a good idea, but they might want to reexamine it. What might appear like calm and steadfast behavior from their perspective is starting to look, from the outside, like the actions of a company with something to hide. This is America, guys. We talk about things over here; you can't shut us up. Join the party.
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October 4, 2006
The Kornberg Nobel seems to have set off some "whither chemistry" noises over here (see the comments to this post). I wanted to highlight an especially provocative one:
Derek, I hope I don't offend my chemist colleagues (I'm myself a former chemist), but as a chemist you have to realize that Chemistry is a science of a lesser public impact. Done at the edges of important matters, it's physics, done at the edges of interesting issues, it becomes biology. You ask for the final explanation of matter and energy and you are a physicist, you are interested in the beauty and complexity of life, you are a biologist. Sorry, chemistry is a practical science, but today its mostly a set of tools.
Hey, I did say it was provocative. As you'd guess, I don't agree, but that doesn't mean that I don't understand this point of view. There seem to be a fair number of chemists with similar sinking feelings, to judge from the letters that show up from time to time in Chemical and Engineering News. The problem is, the same argument by exclusion slice-and-dice can be applied to any other scientific discipline, so long as you define its edges by labeling the things around it as "important" and "interesting".
I could turn things the other way by wondering if, then, some of the important parts of physics are the parts that overlap with chemistry, and some of the most interesting parts of biology are the ones that do likewise. But I don't want to get into a shouting contest about whose work is most useful or exciting, because I don't think it gets us anywhere to talk in those terms.
For me, chemistry is the science that deals with behavior of systems on a molecular level. As you go down to the atomic level, you get into physics (and by the time you're in the subatomic range, you're in physics up to your eyebrows). As you go up from single molecules to larger and larger molecular systems, you start to shade into biology, because the largest and most complicated of those we know about are living organisms.
So rather than bemoan these other disciplines poaching on chemistry's territory, or decide that all the good stuff belongs to them and that chemistry is left with nothing, I'd prefer to think that the field is in an excellent position. We're just at where both those other fields start to get really tough. Look at physics - you can do quantum mechanics on single isolated particles, but once you start bringing in more of them, things get very sticky very quickly. That's why there are all those molecular modeling programs, each full of its own assumptions and approximations, because that's the only way you can approach the calculations at all. Moving up from single particles to atoms and on to molecules is a huge leap in complexity.
And as for biology, the complexity has become more apparent by movement in the other direction. If you thought classical zoology or botany were pretty tangled up, take a look at them on the molecular level! Biology has made tremendous advances through the treatment of its smallest mechanical parts as real molecules behaving chemically. Look at the med-chem concept of a receptor - it was a revelation when people finally realized that this wasn't just a convenient bit of mental shorthand, but a concept that reflected an actual physical entity. And of course, the question of when a collection of molecular machines can be considered a living organism has set off arguments for decades.
No, being in the middle of the range has its advantages. These folks are in our territory because there's so much here to attract them. As chemists, we have to realize this and make the most of it, not sit around moaning about how other people are hogging the spotlight.
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As everyone will have heard, Roger Kornberg has been awarded the chemistry Nobel for his work on RNA polymerase. This is certainly deserved, since his lab has been working on this important area for years, gradually zooming in on the enzyme's structure and function through biological and X-ray methods.
But he wasn't on anyone's short list to win the Chemistry prize, and I doubt if Kornberg considers himself a chemist. For some time now, the Nobel people have been using the prize as an overflow from the Medicine/Physiology area, which this morning led Paul Bracher over at the Endless Frontier blog to call for chemistry to colonize the Physics prize. Kornberg wasn't on his long list of candidates with odds, because most everyone on his list was, well, a chemist.
But it is nice to have another enzyme-studying Kornberg from Stanford with a Nobel. Arthur Kornberg is still alive, and still publishing papers as of a few years ago. I hope he's in good enough health to enjoy his son's achievement.
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October 3, 2006
A lot of people had given up on neuropeptide Y antagonists as potential obesity therapies, but Merck kept the faith. They were enrolling patients in a combination trial with one of their compounds (MK-0557, a Y5 ligand which I believe is this guy) as recently as three years ago, although I believe that all clinical work stopped on the drug sometime in 2005. (See the note on this site from New Zealand; a search within the page for "0557" will turn it up).
Now the post-mortem for the drug has appeared in Cell Metabolism. Nature's news site has a good summary of the story, although they treat it as more of a fresh news bulletin than it really is. In short, the compound can cause statistically significant (but very modest and clinically useless) weight loss.
It joins a large and varied junk heap of obesity compounds (this category has comments on some of them). I'm surprised that Merck was still cranking away on this particular mechanism, but they have a reputation for tenacity. And they also have several other compounds in the clinic, including another CB-1 antagonist as competition for rimonabant. Speaking of which, where is rimonabant? And will it avoid being the largest compound on the same heap?
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October 2, 2006
Every time a Nobel Prize is announced, reporters try to put in some sort of "news you can use" context. That's usually pretty easy to do with the Medicine/Physiology prize, and usually impossible with Physics. Chemistry falls into a middle ground - as opposed to some of the pure-knowledge physics awards, the chemistry discoveries are being used to do something in the physical world, but explaining what that is can be tough.
How did the popular press handle today's award? I invite readers to share any particularly clueless news stories, but most of the the reports I've heard have stressed the potential therapeutic value of RNA interference. There's often been a list of diseases that might be treated, with no particular timeline given, which is a good thing. NPR at least had some disclaimers in there, mentioning near the end that researchers still needed to find a way to dose the compounds, get them to the tissues of interest, make sure that they weren't toxic, and prove that they do affect the diseases they're targeted for.
Minor details, all of 'em. Right? That's just about 85% of drug development right there, actually, and the fact that these can be lumped together at the end of a news segment might be why (among other things) the "government research discovers all the drugs" idea has such staying power. I think that people see all those hard steps without realizing that they're hard . All that stuff about dosing, toxicity, selectivity, it's all what you do in the last few months before you hit the pharmacy shelves, I guess, along with picking a color for the package.
RNA interference is probably going to have a long climb before it starts curing many diseases, because many of those problems are even tougher than usual in its case. That doesn't take away from the discovery, though, any more than the complications of off-target effects take away from it when you talk about RNAi's research uses in cell culture. The fact that RNA interference is trickier than it first looked, in vivo or in vitro, is only to be expected. What breakthrough isn't?
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I'd been predicting for years that RNA interference would be worth a Nobel, and this year the committee did what many expected them to do. But not many people expected them to do it this early - not even Craig Mello himself. And he's being modest in that quote about having an "inkling" that it "might be possible", but that's understandable. Congratulations to him and to Andrew Fire!
I notice that the committee didn't go back as far as the initial observations of the first observations in plants (or in nematodes). The explanation for all these results started with Fire and Mello, and that's where the committee started as well.
Update: Paul Bracher sets the odds for Wednesday's prize in chemistry. I might run some of the numbers a bit differently, but not terribly so, and it's a pretty comprehensive list of possibles.
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October 1, 2006
Are you qualified to be a medicinal chemist? Take this simple quiz!
1. You synthesize a new drug candidate. It won't even dissolve in hot DMSO. Do you. . .
(a) Chuck it into the chemical waste, because it's never going to be a drug
(b) Wonder if it's clean, because you're never going to be able to get it down the LC/MS
(c) Send it in for the assays, because you never know.
2. You've just received the results of a crucial in vivo test of your project's best candidate. It was exactly as active as powdered drink mix. Do you. . .
(a) Blame the animal group for fouling up the dosing
(b) Blame the PK group for fouling up the results
(c) Feel a sense of relief that maybe there's an assay that you might have managed to finally kill
3. Your compound kills mice. But it makes rats fat and happy. Do you. . .
(a) Feel a sense of relief that at least your main tox species is still in the running
(b) Close your eyes, hold your breath, and scale up for the dog
(c) Wonder what it would do to Kevin Trudeau?
4. You need to make a competitor's compound, but their patent synthesis just doesn't work. Do you. . .
(a) Stare out the window, muttering things about disclosure of best mode
(b) Set up a literature alert, hoping for a process patent application to clear things up
(c) Rub your hands together and send the synthesis out to a contract lab, turning it into their problem?
5. Your lab has been assigned a yearly minimum number of analogs for performance review. Do you. . .
(a) Tell your group to send in every intermedidate compound, even the smelly unstable brown ones
(b) Feel a sense of relief that at least they're not asking for a quota of active compounds
(c) Reach for the big bottle of DCC, 'cause if it's amides they want, it's amides they'll get
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