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: firstname.lastname@example.org
January 29, 2010
The crew at Angewandte Chemie has produced another head-shaking pun in one of their latest abstracts. Read only if (1) you know your 1980s music, and (2) you have a high tolerance for wordplay. When I was in Germany, this sort of joke was known as an "eiskalter" and was greeted with shivers.
+ TrackBacks (0) | Category: The Scientific Literature
Xconomy has a look inside the Merck-Sirna acquisition, an interview with Merck's head of that area. As you'd guess, he emphasizes that one of the biggest challenges in the field is delivery, and he makes the pitch that this is how Merck is going to make this work out:
What you often read about, but many people don’t understand, is how hard it is to make a drug. Our approach to RNA Therapeutics is made with a recognition of the full package it takes to launch a successful commercial product. . .That’s versus another strategy you see from smaller companies, which is to get an interesting experimental result, and publicly disclose it in an attempt to increase the value of your investment or a VC’s investment, without a real [awareness] of what it will take to make a therapeutic eight years later. . .
We immediately, after the acquisition, invested not just heavily in the RNA piece that is here in San Francisco, but we built an entire delivery group in West Point, PA. The thing that continues to differentiate Merck is that we have people with decades of experience in pharma R&D, drug safety, metabolism, pharmacokinetics. . .
Outside of RNA as a therapy in itself, he also talks about Merck's use of the technology to better understand its small-molecule targets. It's not something that you'll ever see press releases about, but trustworthy data of that sort is very useful and important. As the Xconomy interviewer notes, Wall Street values this sort of thing as basically zero (partly because you can't see the results of it for quite a while, if they're ever made public at all), but the value inside the company can be significant.
Of course, there can be things that happen inside drug companies that significantly destroy value, too, and it's not like the stock market can see (or understand) many of those, either, but that's a topic for another post entirely. . .and on a not perhaps unrelated note, one part of the interview above seems to suggest that "POS" is an internal Merck acronym for. . .wait for it. . ."probability of success". I, uh, kid you not.
+ TrackBacks (0) | Category: Business and Markets | Drug Assays | Drug Development
I get a lot of press releases around here - not a day goes by that several don't show up in the e-mail queue. I glance over the titles, and I'll open up the more interesting ones and look at them in more detail. Since I feel no obligation to read unsolicited bulk mail (who does?), the less interesting ones get deleted without opening.
Most of what shows up is reasonably well targeted, from university press offices or scientific publishers, and once in a while one of them will lead to a blog post. The PR from small pharma/biotech companies is also probably well targeted, but it's much less likely to lead to anything, simply because there's so much of that stuff around and because it tends, on the average, to be decidedly less interesting: "Spamozyme, Inc. announces its new ZippyChip assay, now with the great taste of fish!" (I don't have the heart to ask Google if "ZippyChip" is the name of a real technology; I fear the answer).
But I also get things that are seriously misguided. Publicists ask me if I want to talk to someone who's just published "Nineteen All-Natural Ways to Quantum Healing" or some damn thing, and the answer is, no, of course I don't. I'd rather drop an Erlenmeyer flask on my foot. Come to that, I'd rather read press releases about the ZippyChip. I know somebody's getting value for their publicity dollar when I get an e-mail pitch asking if my readers would be interested in learning the ways to holistic health without resorting to dangerous and toxic pharmaceuticals
+ TrackBacks (0) | Category: Blog Housekeeping
January 28, 2010
As many had feared, AstraZeneca used their announcement of financial results as the cue to also announce another round of layoffs. I'd been hearing word that this might be coming, but didn't have a line on the size and timing. But it's 8,000 jobs over the next four years, and that Chemistry World link says that 1,800 of them will be in R&D. Another 1,700 R&D jobs will be affected as people and departments move around.
AZ has plenty of patent trouble coming (Crestor's expiration foremost), and plenty of legal bills. So I wouldn't necessarily say that today's announcement will end the layoff process, either, unfortunately. . .
+ TrackBacks (0) | Category: Business and Markets
This information comes to me secondhand, so I'm not sure how accurate it is. I hope it turns out not to be true. A correspondent writes to me that he's spoken this week to someone who had recently been at the former Wyeth site in Princeton, which is in the process of shutting down. The usual practice is for industrial research sites to make surplus equipment available to academic labs and the like, but the report is that this isn't happening in this case.
Instead, glassware is just being broken and tossed, along with a lot of other equipment, and the entire chemical reagent collection is supposedly going to be carted off by a waste disposal firm for incineration. That must be the commercially available stuff on the shelves - sometimes it's not worth the paperwork and trouble to send those on somewhere else, but sometimes it is. But the glassware and equipment definitely shouldn't be going to waste, but from the sound of this report, that's just what's happening.
Can anyone add details to this? Are the people closing down that site really just heaving everything into dumpsters?
+ TrackBacks (0) | Category: Current Events
I had not been following the progress of Acorda's recently approved drug Ampyra for MS. (Well, more specifically, it's to improve gait and walking speed in MS patients). Opinion seems to be rather divided about how successful it'll be. On the one hand, new therapies for multiple sclerosis are certainly needed, but there's also room to argue about just how efficacious Ampyra really is.
I'm not going to fight that one out here, because we'll have the judgment of the market pretty soon. What I find interesting is the structure of this new drug: it's 4-aminopyridine. If there's a more simple, lower molecular weight structure approved within the next few years as an oral drug for anything, I'll be quite surprised.
This brings up several interesting topics relating to drug development and intellectual property. For one thing, this compound has been known for many years as a ligand for neuronal voltage-gated potassium channels, which is the mechanism by which it seems to work for MS patients. Some of these patients have experimented with it themselves over the years; the idea of using it for multiple sclerosis is certainly not new. (Here's a good history, taking things back a good 30 years through many players, with Elan a prominent one).
Secondly, it's not like the compound's chemical structure can be patented as such, either, since it's nowhere near novel. I have no idea of when 4-aminopyridine first makes its appearance in the chemical literature, but it's surely back into the 19th century. Nor is it anything like a rare chemical. For many years it was used as a bird-control poison. (High doses are fatal, but lower ones cause bird seizures that cause the rest of the flock to leave in consternation). We've got some on the shelf in our stockroom; I see in my Aldrich catalog that they're selling the 99% grade for $18/gram. And Aldrich is not exactly the world's low-cost chemical supplier. A railroad car full of the stuff could surely be arranged through someone, although it wouldn't exactly be pharmaceutical grade.
So. . .how then, some might wonder, does Acorda Therapeutics (partnered with Biogen Idec) get to charge several thousand dollars a year for Ampyra? (I don't think the actual price is known yet, but that's the best guess I've seen). One key factor is the bird-repellant aspect. Messing with ion channels in nerves is a tricky business, and 4-aminopyridine can and will cause trouble in humans if it's not dosed carefully. It's also (I believe) cleared pretty quickly, as you'd expect from something with that structure. Ampyra is a time-release formulation, an attempt to get enough of the compound into circulation over a long enough period, but without crossing over the line to too high a concentration, which could set off seizures and worse. Taking 4-aminopyridine from that railroad car and using that instead would be very much not recommended, considering what's waiting out there at inappropriate doses.
And that's Acorda's intellectual property. Plenty of work was done to find a good formulation for the drug, and Acorda spent the time and money to test one for safety and efficacy. They get to reap the fruits of their labors, if fruits there are. And that's what the market will decide for them. . .
+ TrackBacks (0) | Category: Patents and IP | The Central Nervous System
January 27, 2010
It hit me, one day during my graduate career, that I was spending my nights, days, weekends, and holidays trying to make a natural product, while the bacterium that produced the thing in the first place was sitting around in the dirt of a Texas golf course, making the molecule at ambient temperature in water and managing to perform all its other pressing business at the same time. This put me in my place. I've respected biosynthesis ever since.
But there are some areas where we humans can still outproduce the small-and-slimies, and one of those is in organofluorine compounds. Fluorine's a wonderful element to use in medicinal chemistry, since it alters the electronic properties of your molecule without changing its shape (or adding much weight), and the C-F bond is metabolically inert. But those very properties can make fluorination a tricky business. If you can displace a leaving group with fluoride ion to get your compound, then good for you. Too often, though, those charges are the wrong way around, and electrophilic fluorination is the only solution. There are heaps of different ways to do this in the literature, which is a sign to the experienced chemist that there are no general methods to be had. (That's one of my Laws of the Lab, actually). The reagents needed for these transformations start with a few in the Easily Dealt With category, wind entertainingly through the Rather Unusual, and rapidly pile up over at the Truly Alarming end.
But at least we can get some things to work. The natural products with fluorine in them can be counted on the fingers. A fluorinase enzyme has been isolated which does the biotransformation on
4-fluorothreonine S-adenosyl methionine (using fluoride ion, naturally - if an enzyme is ever discovered that uses electrophilic F-plus as an intermediate, I will stand at attention and salute it). And now comes word that this has been successfully engineered into another bacterial species, and used to produce a fluorine analog of that bacterium's usual organochlorine natural product.
It isn't pretty, but it does work. One big problem is that the fluoride ion the enzyme needs is toxic to the rest of the organism, so you can't push this system too hard. But the interest in this sort of transformation is too high (and the potential stakes too lucrative) to keep it from being obscure forever. Bring on the fluorinating enzymes!
+ TrackBacks (0) | Category: Biological News
Now here's a weird one. The San Diego diagnostics company Sequenom came up with a non-invasive test for Down's Syndrome,
and sold it to another outfit, Xenomics, for development. Update: I've got this transfer backwards - Xenomics licensed some of its nucleic acid technology to Sequenom, and has now regretted it. But late last year, things unraveled spectacularly. In April, Sequenom announced that there were problems with the test and announced that it had launched an internal investigation. In September came the unwelcome news that the data backing up their product were (quoting here) "inadequately substantiated". And they meant it, too, as the CEO and six other higher-ups all left the company under a cloud of confusion, recrimination, and very bad acronyms (like SEC and FBI). Last week it settled a dozen shareholder lawsuits over the whole affair.
But as that story at Bnet makes clear, the terms of the settlement were rather alarming, with Sequenom promising to do things like. . .make sure that everyone involved knew which studies were blinded and which weren't. And requiring bar-codes on the tissue sample vials. And not giving everyone access to the storage room where they were all kept. And. . .well, you get the idea. It's like seeing a sign at the burger place that says "Healthy Choice - Now With 30 Per Cent Less Aardvark Meat! And Try Our New No-Salmonella Menu!"
It can always get worse, though. Now Xenomics is suing, claiming that not only were the data weak and the controls insufficient, but that there never was a test in the first place. The complaint (available as a PDF at that link) is pretty zippy stuff by legal standards, featuring phrases such as "Defendant maintained the charade that it had. . ."
Way before all this lunacy, some people were skeptical about the company's prospects even if things went well. But hey, let's not dwell on the negatives here. If you'd like "Three Reasons to Buy Sequenom Today", this guy has them. I think I'll let this opportunity slip past, personally.
+ TrackBacks (0) | Category: Analytical Chemistry | Business and Markets | The Dark Side
January 26, 2010
So says GlaxoSmithKline CEO Andrew Witty about the Sirtris controversy - see this Forbes story for more. I hope he's right. I actually would like to see good things come out of sirtuin research - the biology's clearly interesting enough. And I would like to think that GSK didn't blow $720 million, because we could all use that sort of money these days. This story will only be settled for sure in the clinic, with the agents the GSK is developing. Good luck to them. I fear that they might need it, but I hope that they don't.
+ TrackBacks (0) | Category: Aging and Lifespan
Yesterday's post touched on something that all experienced drug discovery people have been through: the compound that works - until a new batch is made. Then it doesn't work so well. What to do?
You have a fork in the road here: one route is labeled "Blame the Assay" and the other one is "Blame the Compound". Neither can be ruled out at first, but the second alternative is easier to check out, thanks to modern analytical chemistry. A clean (or at least identical) LC/MS, a good NMR, even (gasp!) elemental analysis - all these can reassure you that the compound itself hasn't changed.
But sometimes it has. In my experience, the biggest mistake is to not fully characterize the original batch, particularly if it's a purchased compound, or if it comes from the dusty recesses of the archive. You really, really want to do an analytical check on these things. Labels can be mistaken, purity can be overestimated, compounds can decompose. I've seen all of these derail things. I believe I've mentioned a putative phosphatase inhibitor I worked on once, presented to me as a fine lead right out of the screening files. We resynthesized a batch of it, which promptly made the assay collapse. Despite having been told that the original compound had checked out just fine, I sent some out for elemental analysis, and marked some of the lesser-used boxes on the form while I was at it. This showed that the archive compound was, in fact, about a 1:1 zinc complex, for reasons that were lost in the mists of time, and that this (as you can imagine) did have a bit of an effect on the primary enzyme assay.
And I've seen plenty of things that have fallen apart on storage, and several commercial compounds that were clean as could be, but whose identity had no relation to what was on their labels (or their invoices for payment, dang it all). Always check, and always do that first. But what if you have, and the second lot doesn't work, and it appears to match the first in every way?
Personally, I say run the assay again, with whatever controls you can think of. I think at that point the chances of something odd happening there are greater than the chemical alternative, which is the dreaded Infinitely Active Impurity. Several times over the years, people have tried to convince me that even though some compound may look 99% clean, that all the activity is actually down there in the trace contaminants, and that if we just find it, we'll have something that'll be so potent that it'll make our heads spin. A successful conclusion to one of these snipe hunts is theoretically possible. But I have never witnessed one.
I'm willing to credit the flip side argument, the Infinitely Nasty Impurity, a bit more. It's easier to imagine something that would vigorously mess up an assay, although even then you generally need more than a trace. An equimolar amount of zinc will do. But an incredibly active compound, one that does just what you want, but in quantities so small that you've missed seeing it? Unlikely. Look for it, sure, but don't expect to find anything - and have 'em re-run that assay while you're looking.
Update: I meant to mention this, but a comment brings it up as well. One thing that may not show up so easily is a difference in the physical form of the compound, depending on how it's produced. This will mainly show up if you're (for example) dosing a suspension of powdered drug substance in an animal. A solution assay should cancel these things out (in vitro or in vivo), but you need to make sure that everything's really in solution. . .
+ TrackBacks (0) | Category: Analytical Chemistry | Drug Assays | Life in the Drug Labs
January 25, 2010
Nature has a short item on the Pfizer paper that questions the reproducibility of some key sirtuin work (covered here and here). There are some good points to temper the pessimism. Leonard Guarente of MIT, a key pioneer in the field, says:
". . . that the latest findings are neither surprising nor worrisome. The compounds may work only with fluorophore-conjugated peptides in vitro, says Guarente, but the situation is different in cells and in animals. The Nature paper, among others, went beyond the test tube and indicated that SIRT1 was more active in cells and in animals after application of the Sirtris compounds. Furthermore, resveratrol administration made no difference to the lifespan of yeast that did not have Sir23, indicating that the compound's action depends on this gene.
According to a statement from GlaxoSmithKline, Ahn's conclusion "ignores any possibility of direct activation of SIRT1 that may occur in a cellular environment that is not reproduced in vitro".
True, but there's still that problem of the Pfizer group not being able to reproduce the in vivo effects, which to me was perhaps the most worrisome part of the paper. Now, it's worth remembering that animal studies are not the easiest things in the world to do right, since there are so many variables. Small differences in animal strains and the like can sometimes throw things off severely. Even the Pfizer group admits this readily, with Kay Ahn telling Nature that "every in vivo experiment is a little bit different" and that "Under our conditions we didn't see beneficial effects, but we don't want to make a big conclusion out of those results."
That's an honorable way to put things, I have to say. Rather less honorable, though, at least to me, is David Sinclair's response from the Sirtris team. See what you think:
A possible explanation for the discrepancy, says Sinclair, is that Ahn and her colleagues did not provide information on the characterization of the compounds, which they synthesized themselves. So there is no way of knowing how pure they were or whether they're the same as those made by Sirtris. "The fact that mice died indicates that there may be an issue with purity,".
That's. . .not so good. In fact, it comes close to being insulting. Although I say a lot of uncomplimentary things about Pfizer's management, the fact remains that they have a lot of very good scientists there. And I assume that they can reproduce Sirtris's published procedures to make the sirtuin ligands. If they can't, frankly, that's Sirtris's fault. Everyone (well, everyone competent) checks out compounds thoroughly before putting them into an animal study. Asking "Are you sure you made the right stuff?" at this point is really a bit much, and doesn't do anything improve my opinion of Sirtris. (Which opinion actually was pretty good - until recently).
+ TrackBacks (0) | Category: Aging and Lifespan | Drug Assays
January 22, 2010
I've written here before about how I used to think that I understood G-protein coupled receptors (GPCRs), but that time and experience have proven to me that I didn't know much of anything. One of the factors that's complicated that field is the realization that these receptors can interact with each other, forming dimers (or perhaps even larger assemblies) which presumably are there for some good reason, and can act differently from the classic monomeric form.
A neat paper has appeared in PNAS that gives us some quantitative numbers on this phenomenon, and some great pictures as well. What you're looking at is a good ol' CHO cell, transfected with muscarinic M1 receptors. Twenty years ago (gulp) I was cranking out compounds to tickle cell membranes of this exact type, among others. The receptors are visualized by a fluorescent ligand (telenzepine), and the existence of dimers can be inferred by the "double-intensity" spots shown in the inset.
With this kind of resolution and time scale, the UK team that did this work could watch the receptors wandering over the cell surface in real time. It's a classic random walk, as far as they can tell. Watching the cohort of high-intensity spots, they can see changes as they switch to lower-intensity monomers and back again. Over a two-second period, it appeared that about 81% of the tracks were monomers, 9% were dimers, and 3% changed over during the tracking. (The remaining 7% were impossible to assign with confidence, which makes me wonder what's lurking down there).
They refined the technique by using two differently-fluorescent forms of labeled telenzepine, labeling the cells in a 50/50 ratio, and watching what happens to the red, green, (and combined yellow) spots over time. It looks as if the receptor population is a steady-state mix of monomers and dimers, exchanging on a time scale of seconds. Of course, the question comes up of how different ligands might affect this process, and you could begin to answer that with different fluorescent species. But since the technique depends on having a low-off-rate species bound to the receptor in order to see it, some of the most intere