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
June 30, 2009
Sanofi is saying "no layoffs" in their announcement today, but is instead counting on "voluntary staff departures". Here's the press release, courtesy of Fierce Biotech, notable for its relentless insistence on not capitalizing the name of the company.
I'm not sure how those voluntary departures are supposed to work - I can tell you it would take a lot to get anyone in R&D to volunteer to leave their job in this climate. So, generous - very generous - buyouts are one way, and sheer attrition is another (although turnover must not be so high these days either, with fewer places to go). The press release is rather short on details. Don't believe me? Chew on this:
"To implement this new R&D model, sanofi-aventis will group researchers in more productive structures and engage in recruiting and training to adapt the profiles and skills of its collaborators to the demands of these mutations. The model also includes strengthening 'exploratory structures' that work in close collaboration with outside entities and deploying reactive 'entrepreneurial units' to encourage the emergence of innovation and accelerate the marketing of innovative products."
Well, OK, then! I guess we'll have to wait some more for this fog to condense into something recognizable.
+ TrackBacks (0) | Category: Business and Markets
Organic synthesis as we know it can't go on without metal-catalyzed bond-forming reactions. There are too many of them, and they're just too useful. Palladium's the workhorse, followed by copper, then you've got rhodium, nickel, and a host of others (gold's been popular the last few years). We have a. . .fairly good idea of what's going on in these reactions, but not quite good enough. If we really understood all the factors involved, there wouldn't be six garbonzillion different sets of conditions for these things, would there?
A short paper's just come out in Angewandte Chemie that illustrates some of the trickiness involved. Carsten Bolm's group at Aachen has published several interesting iron-catalyzed coupling reactions using good old ferric chloride. These are aryl-amine, aryl-ether, aryl-amide and aryl-sulfide-forming procedures, which cover a lot of ground. (Interestingly, it was one of those sulfide papers that was recently plagiarized by another set of authors). But there were always a few kinks, such as variable yield depending on which bottle of ferric chloride was used.
Well, organometallic chemists are used to that sort of thing. But Bolm has gone back to look at things closely, in collaboration with Stephen Buchwald of MIT (whose group has published many similar couplings with other metal systems), and found a surprise. The iron chloride isn't doing a thing. In fact, as you go to more and more pure sources of the reagent, the yield drops off. But it never goes away, even with the 99.9% pure stuff. That's because it seems to be copper (I) contaminants doing the coupling, even at the parts-per-million level.
There are some startling tables in the paper. For coupling pyrazole onto an aryl iodide, for example, Bolm's group had found in 2007 that they could get 87% yield using >98% ferric chloride from E. Merck, along with dimethylethylene diamine as a cosolvent. If you use the >98% from Aldrich under the same conditions, though, you get 26% yield. And the Aldrich >99.99 stuff gives you only 9%. But if you add five ppm copper (I) oxide to that last reaction, the yield goes up to 78%. And if you leave the ferric chloride out completely, and just go with a trace of copper, the yield is exactly the same (it goes down if you run the same trace-of-copper without the diamine, which seems to be complexing it up into solution).
The other couplings that were reported seem to follow the same pattern. This must really be a disappointment to Bolm and his group, because their work was, among other things, an attempt to get away from copper and palladium. Still, this appears to be a much cleaner and more efficient copper reaction than a lot of the procedures out there.
This sort of thing has happened before in organometallic chemistry. There's a well-known example of nickel contamination in a chromium-mediated reaction from the mid-1980s, and more recently, a report of supposed "metal-free" couplings which appear to have been catalyzed by parts-per-billion levels of palladium found in the sodium carbonate being used as a base, of all things. Tricky things, these metals.
+ TrackBacks (0) | Category: Chemical News
June 29, 2009
Not long ago, I wrote about a Pfizer program for smaller companies to come screen their targets against Pfizer's compound bank. Now Eli Lilly has flipped that around. In an initiative to bring other people's compounds out of the stockrooms and off the shelves, they'll screen them for free.
These aren't single-target assays. The company has four phenotypic screens going (for Alzheimer's, diabetes, cancer, and osteoporosis) and will look for improvement by any mechanism that comes to hand. No chemical structure information is shown to Lilly (I assume that they just know the molecular weight so they can run a dilution series). If something looks interesting, the company and the owners of the chemical matter have 120 days to come to terms for any further development deal - if not, then all rights revert to the submitter, and they can publish the data from the screens.
Lilly's working out a universal material transfer agreement, in collaboration with a number of universities, so that the paperwork stays the same every time. That's a good move. The lawyering can be a real holdup - in my experience, every party in these agreements usually comes in with slightly different wording in their magic legal spells, requiring several rounds of reconciliation before everyone's ready to sign.
I think that this is a worthwhile idea, and that they'll get a lot of takers. There are plenty of compounds sitting around in academic labs gathering dust, so why not send 'em in? The worst that can happen is nothing, and the best is that the compound actually turns out to be worth something. But will anything come out of it? The closest program to this is surely the National Cancer Institute's long-standing (since 1990) NCI-60 screening program, which also runs at no cost to the submitters. Even so, a recent reference mentions that there are between 40,000 and 50,000 compound in the NCI database, which actually seems rather small, considering. (To be fair, the program is not being funded at the levels that it was during the early 1990s). The only marketed compound that I'm aware of that can be said to have come out of the NCI-60 screen is Velcade (bortezomib), known then as PS-341, which was sent in for screening by Proscript Pharmaceuticals in the mid-1990s. Many other interesting structures have turned up along the way, though, which for various reasons haven't made it all the way through.
It'll be quite interesting to see what sort of hit rate Lilly's phenotypic assays call up - I hope they tell us. I have a lot of sympathy for the mechanism-agnostic approach myself, and I'd like to see how closely my bias are aligned to reality.
+ TrackBacks (0) | Category: Drug Assays | Drug Development
June 26, 2009
I missed commenting on this earlier, but many readers may have noticed the recent scandal caused by Zicam. This is a cold remedy which was sold as a homeopathic medicine, but its makers committed the unforgivable sin of actually having something in its formula besides well-shaken distilled water.
A lot of people are convinced that zinc is good for colds - I'm agnostic, having not seen much convincing evidence - so if that's the case, why not snort zinc up your nose? That, at any rate, seems to be the condensed version of the Zicam pitch, although I don't believe that they used that exact wording in their ads. (A gift for advertising copy might not be one of my more robust talents. . .) At any rate, snorting zinc salts has actually been known, for some time now, to injure the sense of smell in some people. So it's proved with Zicam, with several hundred victims.
The moral? If you're going to sell homeopathic medicine - and boy, is it a lucrative business - make sure that you don't put anything in there except sterile water. That'll cut down on your expenses, too, since most ingredients cost more than water, anyway. Stick with that strategy, and you can be absolutely sure that nothing bad will happen to your customers. Nothing good will happen to them either, but they won't know that. When their cold/headache/whatever goes away of its own accord, they'll ascribe it to your miracle product. Sit back and profit! Be sure to thank Senator Hatch while you count your money, though - it's only proper.
+ TrackBacks (0) | Category: Regulatory Affairs | Snake Oil
June 25, 2009
Via a reader comes this article, which takes us to Elsevier's hard-hitting textbook publishing operation. The co-authors of a psychology text for the publisher were recently taken aback to get this e-mail from a publicist at the company:
""Congratulations and thank you for your contribution to Clinical Psychology. Now that the book is published, we need your help to get some 5 star reviews posted to both Amazon and Barnes & Noble to help support and promote it. As you know, these online reviews are extremely persuasive when customers are considering a purchase. For your time, we would like to compensate you with a copy of the book under review as well as a $25 Amazon gift card. If you have colleagues or students who would be willing to post positive reviews, please feel free to forward this e-mail to them to participate. We share the common goal of wanting Clinical Psychology to sell and succeed. The tactics defined above have proven to dramatically increase exposure and boost sales. I hope we can work together to make a strong and profitable impact through our online bookselling channels."
George Tremblay of Antioch U. blew the whistle on this one, which is a good deed. But, cynical person that I am, it makes me wonder how many others on the list might have been ready to pitch in. And given that this has apparently been done before (hey, this is a "proven" strategy), you also have to wonder about five-star reviews of other textbooks published by Elsevier. And other houses, too?
I ask because the company's director of public relations has come out to explain just where this latest tactic went too far - and I have to say, it's a bit further along the line than many people might have thought:
"Encouraging interested parties to post book reviews isn't outside the norm in scholarly publishing, nor is it wrong to offer to nominally compensate people for their time, some of these books are quite large," he said. "But in all instances the request should be unbiased, with no incentives for a positive review, and that's where this particular e-mail went too far."
So when you're encouraging people to write reviews, and offering them some baksheesh for doing so, that's fine. You just don't want to be so gauche as to actually come out and say that you want the reviews to be positive. This does not make Elsevier look good, of course, coming as it does after the reheated-tray-of-friendly-leftovers journal scandal in Australia. (And let's not forget the, um, unusual case of El Naschie and his private Elsevier journal of nonsense). They either are the poor victims of widely scattered unethical promotions staff, or (just perhaps) there's a general culture in that department that allows people to think that these things are acceptable practice.
+ TrackBacks (0) | Category: The Dark Side | The Scientific Literature
June 24, 2009
There's a lot of talk that something big is going to happen at Sanofi-Aventis next week. What we don't know is whether this is a sales-and-marketing change, a mostly-European change, or what. The company's been through layoffs already, but hey, in this climate, who hasn't? More on this as something reliable emerges. . .
+ TrackBacks (0) | Category: Business and Markets
There are some interesting statements from GlaxoSmithKline CEO Andrew Witty here at Reuters. He admits that morale was completely in the scupper around the place a few months ago, which certainly seems to be true, but says that they're turning things around. To that point, remember all that stuff a few years ago about how GSK's research structure exemplified pretty much everything that a drug company needed to have? Well. . .
"We've really thrown into reverse much of the trend of research organisation that had developed over the last 15 years," Witty said.
Over that time, the drugs industry was a big commercial success but it took a "wrong turn" by deciding that drug discovery was an industrial process based on large-scale application of technologies like genomics, proteomics and combinatorial chemistry.
"These were all supposed to transform productivity yet none of them did. It turns out, in my view, that research is much more of an art than a science," Witty said.
Several thoughts come to mind. First off, I take the point about art versus science, but it's hard to do art on an industrial scale. That, to my mind, has been one of the major problems in all of drug R&D. He's right that the industry keeps seizing on things that promise to take some of the craziness out of the process - but it's not like the temptation isn't still around. We just haven't seen the latest brainwave yet.
But still, over time, some of the random element has decreased. We actually do understand a lot of things better than we used to. We know to look for hERG, to pick one example, and there are others. But these things don't (yet) add to enough of a transformation. Adding more and more knowledge to the pile has to help - I'm certainly not enough of a nihilist to deny that - but it's fair to say that it hasn't helped as quickly and as thoroughly as we might have hoped.
You can find opinions all up and down that spectrum: at one end are the nihilists themselves, who hold that the problems we're trying to solve are (at present) too hard, and what's more, they're likely to remain too hard for the foreseeable future, so you'd better get lucky - and design your research structure to improve your chances of doing that. Moving up from there, you have a lot of people in the middle who see incremental progress, but (with Goethe) worry that "Where there is much light, there is much darkness". Every new advance untangles a few things, but also ends up illustrating how much more we need to know. Opinions in this crowd vary, from pessimists who come close to the first nihilist group, all the way up to optimists who hold out hope that things will start making more sense soon. And past them, you come to the super-optimists, the Kurzweilians who are waiting for the Singularity.
But finally, reading the Witty article, I can't help but imagine an interview in around 2020, with whoever's in charge then talking about how they had to get rid of all that musty old research structure that the previous management team had put in. . .
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
June 23, 2009
I appreciate the mail I've had on this subject, and wanted to provide a brief update for those who are interested. If you've set up a proxy server for Iran, you can submit it here - Austin Heap is the guy running this part of the effort. There's also a test page where you can see if you have things configured correctly. Anyone needing more technical details, please drop me a note - I'll either answer it myself or send you on to someone who can. I am, truth be told, not exactly one of the 1337-est haxors around, but one does what one can.
+ TrackBacks (0) | Category: Blog Housekeeping | Current Events
What's really going on with Medarex and ipilimumab? The company made news over the weekend with a press release from the Mayo Clinic, detailed what appears to be a substantial response in two prostate cancer patients. But the more you look at the story, the harder it is to figure out anything useful.
As this WebMD piece makes clear, this study is not a trial of ipilimumab as a single agent. The patients are undergoing prolonged androgen ablation, the testosterone-suppressing therapy that's been around for many years and is one of the standard options for prostate cancer. The trial is to see if ipilimumab has any benefit when it's added to this protocol - basically, to see if it can advance the standard of care a bit.
WebMD quotes Derek Raghavan at the Cleveland Clinic as saying that androgen ablation can sometimes have dramatic results in patients with locally advanced prostate cancer, so it's impossible to say if ipilimumab is helping or not. That's why we run clinical trials, you know, to see if there's a real effect across a meaningful number of patients. But (as this AP story notes) we don't know how many patients are in this particular study, what its endpoints are, or really anything about its design. All we know is that two patients opted out of it for surgery instead. (Credit goes to the AP's Linda Johnson for laying all this out).
Ipilimumab is an antibody against CTLA-4, which is an inhibitory regulator of lymphocytes. Blocking it should, in theory, turn these cells loose to engage tumor cells more robustly. (It also turns them loose to engage normal tissue more robustly, too - most of the side effects seem to be autoimmune responses like colitis, which can be very severe. The antibody has been studied most thoroughly in melanoma, where it does seem to be of value, although the side effect profile is certainly complicating things.
So overall, I think it's way too early to conclude that Medarex has hit on some miracle prostate cure. This press release, in fact, hasn't been too helpful at all, and the Mayo people really should know better.
+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | Toxicology
The In Vivo Blog has a piece that everyone who follows small-company press releases should read. "When Is a Billion Dollars Not a Billion Dollars?", they ask. And the answer is, of course, when someone's press-releasing it. Read the whole thing, but here's the short form: when someone says "We just signed a deal worth a billion dollars!", too often they're leaving out the rest of the sentence. It's supposed to continue like this: ". . .if every single thing goes perfectly and all our drugs work and become the biggest successes they possibly can." And since that happens, like, all the flippin' time, well. . .
+ TrackBacks (0) | Category: Business and Markets | Drug Development
June 22, 2009
Earlier this month I posted about rolofylline, which I noted has a rather unusual noradamantane attached to it. Now check out this ORL-1 compound from Banyu, complete with the not-so-widely-heard-of bicycloheptane-spirocyclopropane group.
This was not arrived at lightly, as you'd imagine. There's a table in the Supporting information for the paper, but I'll quote from the body of the main manuscript:
Various kinds of cycloalkanes, substituted or nonsubstituted cyclopropyl rings to medium sized rings (such as cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl), spiroalkane (such as spiro[2.5]octanemethyl, spiro[3.5]nonanemethyl, spiro[4.5]decanemethyl, spiro[2.4]heptanemethyl, spiro[3.4]octanemethyl, spiro[4.4]nonanemethyl), bicycloheptane (such as methylbicyclo[2.2.1]heptylmethyl, dimethylbicyclo[2.2.1]heptylmethyl, spirocyclopropanebicycloheptanemethyl), and branched alkanes (such as 3,3-dimethylbutane, 3,3-dithylbutane, 1-methylcyclobutaneethyl, 1-methylcyclopentaneethyl, 1-methylcyclohexaneethyl) were tested.
No, that couldn't have been a lot of fun. Anyone else out there found themselves having to optimize grease recently?
+ TrackBacks (0) | Category: Drug Development | Life in the Drug Labs
We organic chemists have it easy compared to the cell culture people. After all, our reactions aren't alive. If we cool them down, they slow down, and if we heat them up, they'll often pick up where they left off. They don't grow, they don't get infected, and they don't have to be fed.
Cells, though, are a major pain. You can't turn your back on 'em. Part of the problem is that there are, as yet, no cells that have evolved to grow in a dish or a culture bottle. Everything we do to them is artificial, and a lot of it what we ask cultured cells to do is clearly not playing to their strengths. Ask Genzyme: they use the workhorse CHO (Chinese Hamster Ovary) cells to produce their biologics, but they've been having variable yield problems over the past few months. Now it turns out that their production facilities are infected with Vesivirus 2117 - I'd never heard of that one, but it interferes with CHO growth, and that's bringing Genzyme's workflow to a halt. (No one's ever reported human infection with that one, just to make that clear).
I assume that the next step is a complete, painstaking cleanup and decontamination. That's going to affect supplies of Cerezyme (imiglucarase) and Frabazyme (agalsidase) late in the summer and into the fall, although it's not clear yet how long the outage will be. Any cell culture lab that's had to toss things due to mycoplasms or other nasties will sympathize, and shudder at the thought of cleaning things up on this scale.
+ TrackBacks (0) | Category: Biological News | Drug Development
June 19, 2009
Anyone who needs pointers on setting up an Iran proxy server, drop me an e-mail; I'll send over the information. There are quite a few technical updates, but I'll only inflict them on those who need 'em. And as for this news story, the Boston Globe reporter asked me "Hey, you're that In the Pipeline guy", aren't you?"
+ TrackBacks (0) | Category: Current Events
After yesterday's post on pathway patents, I figured that I should talk about high-throughput screening in academia. I realize that there are some serious endeavors going on, some of them staffed by ex-industry people. So I don't mean to come across as thinking that academic screening is useless, because it certainly isn't.
What is probably is useless for is enabling a hugely broad patent application like the one Ariad licensed. But the problem with screening for such cases isn't that the effort would come from academic researchers, because industry couldn't do it, either: Merck, Pfizer, GSK and Novartis working together probably couldn't have sufficiently enabled that Ariad patent; it's a monster.
It's true that the compound collections available to all but the very largest academic efforts don't compare in size to what's out there in the drug companies. My point yesterday was that since we can screen those big collections and still come up empty against unusual new targets (again and again), that smaller compound sets are probably at even more of a disadvantage. Chemical space is very, very large. The total number of tractable compounds ever made (so far) is still not a sufficiently large screening collection for some targets. That's been an unpleasant lesson to learn, but I think that it's the truth.
That said, I'm going to start sounding like the pointy-haired boss from Dilbert and say "Screen smarter, not harder". I think that fragment-based approaches are one example of this. Much smaller collections can yield real starting points if you look at the hits in terms of ligand efficiency and let them lead you into new chemical spaces. I think that this is a better use of time, in many cases, than the diversity-oriented synthesis approach, which (as I understand it) tries to fill in those new spaces first and screen second. I don't mind some of the DOS work, because some of it's interesting chemistry, and hey, new molecules are new molecules. But we could all make new molecules for the rest of our lives and still not color in much of the map. Screening collections should be made interesting and diverse, but you have to do a cost/benefit analysis of your approach to that.
I'm more than willing to be proven wrong about this, but I keep thinking that brute force is not going to be the answer to getting hits against the kinds of targets that we're having to think about these days - enzyme classes that haven't yielded anything yet, protein-protein interactions, protein-nucleic acid interactions, and other squirrely stuff. If the modelers can help with these things, then great (although as I understand it, they generally can have a rough time with the DNA and RNA targets). If the solution is to work up from fragments, cranking out the X-ray and NMR structural data as the molecules get larger, then that's fine, too. And if it means that chemists just need to turn around and generate fast targeted libraries around the few real hits that emerge, a more selective use of brute force, then I have no problem with that, either. We're going to need all the help we can get.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development
June 18, 2009
Nature Biotechnology has a good wrap-up of the Ariad patent case, and it includes some insights into the whole "patent the pathway and profit" mindset. That was the heart of Ariad's strategy: they licensed a patent on NF-kappaB from Harvard, MIT, and the Whitehead institute, and promptly went wild threatening to sue everyone that came within a mile of its already ridiculously vast) claims.
I particularly like this description of the legal process involved:
. . .Despite the earlier jury verdict in Ariad's favor, "the federal circuit [court] treated these claims, you know, almost derisively. They just smacked them," says Minnesota patent attorney Warren Woessner, former chair of the biotech committee of the American Intellectual Property Law Association. Woessner had predicted Ariad's defeat. "They won in a jury trial—big deal. They got some Nobel prizewinners up there to say how wonderful this was, and the jury folded like a cheap lawn chair. That's not uncommon. But the [appeals judges] just demolished this."
Indeed. But the strategy isn't dead yet, unfortunately:
Companies asserting broad claims "are not going to get much sympathy" from the federal circuit, agrees (Duke's Arti) Rai. "And if they're trying to assert them against a defendant who is as willing to fight as Eli Lilly is, they're ultimately going to lose."
Many universities, however, emboldened by Ariad's 2006 district court victory, have been pressing for such broad claims. "Every professor that discovers a mechanism of action now wants you to claim it," says Woessner, who advises universities. "And it can be hard to dissuade them from that." The take-home lesson from the Ariad case, says Woessner, is that filing such broad claims, without specifying compounds, hoping that some will stand, is a risky patent strategy. "Don't try to get broad functional claims, like the Ariad claims, or the Rochester claims," he says, without describing specific pathway modulators.
Ah, but coming up with specific pathway modulators is often the job of. . .(drumroll) a drug company. One that's full of medicinal chemists who know how to try to optimize these things. Unless an academic group gets lucky in screening a smaller commercial compound collection, they're not likely to be able to show such enabling compounds. And since most academic researchers don't have access to anything like the industry's high-throughput screening technology, let alone the industry's files of plausible-looking molecules, the chances aren't good. Heck, they aren't all that good for us over here, and we have all those things. To get the full flavor, you really need to see some big HTS campaigns rummage expensively through a whopping compound collection and still come up with only 3-hydroxy-diddleysquat. . .
+ TrackBacks (0) | Category: Patents and IP
June 17, 2009
Just a quick update to my post the other day on proxies for the Iranian protestors. The San Francisco Chronicle has an article on Austin Heap, the fellow whose web site I linked to the other day. He and a number of collaborators are doing a lot of hard work trying to keep lines of communication open from inside Iran.
If any of you are trying the proxy server thing (as I am with my home machine), be sure to check this update. You'll need to make some adjustments, since the (current!) Iranian government isn't making this easy, naturally.
There are other information tunnels, which rapidly get to be beyond my own hardware resources and hacking skills, but many people seem to be at work on these. One interesting addition to the fray is the anti-Scientology group known as Anonymous. Since my opinion of Scientology is nearly as low as my opinion of the Iranian government, I can only welcome this meeting of the minds.
+ TrackBacks (0) | Category: Current Events
There's a good article from Lee Howard up at The Day (the New London/Groton newspaper) on the changes going on at Pfizer. It's the story according to management, though, which is worth having for its compare-and-contrast uses:
Despite the looming uncertainty, according to company spokesmen, the new research structure has added energy and urgency to the drug-discovery process in Groton. . .
. . .The changes in Groton - seen most plainly in displays of logos the new business units are in the process of choosing - have added drug-development staff and even legal experts to the R&D mix, along with biologists and chemists who typically have worked in close proximity. In the middle of it all sits the chief scientific officer of each business unit, as well as other managers.
The idea is to develop a more realistic idea of a drug's likelihood to succeed at an early stage and then bring it to market quicker if it seems to be working.
I hope that the process of choosing new logos doesn't take too long. You could get a reasonable read on the success of any attempt to remake Pfizer's culture by counting the number of meetings the logo process has required so far.
But I can't make fun of the goals that the company is setting - they're perfectly sensible. The only problem is that they're just what everyone else is trying to do, too, and if it were easy, everyone would be finished doing them by now. The problem with trying to get an earlier decision of a drug's chances for success are that many of the serious problems don't show up (in fact, can't show up) until larger clinical trials. And I don't think that anyone's got a good way around that one yet. Some therapeutic areas are better suited than others, to be sure.
Would the new structures that Pfizer's putting in place have prevented the torcetrapib disaster? I doubt it - that one took everyone by surprise. Would they have prevented the Exubera disaster? Now, that one's food for thought, because it seemed to be much more self-inflicted. If the company can avoid doing that sort of thing again, then they've accomplished something.
And for all the nasty things I say about Pfizer here, I hope that they do accomplish things. After all, they're the biggest drug company in the world, and they seem determined to stay that way. If an organization that huge ends up spinning its wheels (or sitting around designing new business cards), it can't be good for anyone.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History
June 16, 2009
Many thanks to the people who've e-mailed me about the situation in Iran. My wife's relatives there are all OK (so far!); she's spoken to them several times. Things remain unstable and impossible to predict. It's been thirty years since huge crowds marched through the streets shouting "Death to the Dictator", so everyone's a bit out of practice.
One thing that the more technically inclined readers might consider doing is setting up proxy servers for use by the Iranian protesters. Two web sites that will give you details on this are here and here. The government is blocking all the obvious IP addresses for people trying to organize and get news out of the country, but anonymous proxies provide a lot of non-obvious routes onto the net. I'm trying to get something set up at home myself.
There are a lot of punches being thrown by both sides - for example, some people with proxy servers have reported a lot of denial-of-service garbage coming in from blocks of Russian and Chinese IP addresses. But if you configure things to accept only Iranian domains (those sites above have IP address lists) you should be able to screen that stuff. If you're up for it, please consider helping out. It's one of the few concrete steps I can think of from this distance. A general guide to the current cyberwarfare situation is here. Update - link went dead, but this new one will stay alive. BoingBoing has enough bandwidth!
+ TrackBacks (0) | Category: Blog Housekeeping | Current Events
June 15, 2009
Yesterday's post on so-called "ugly" molecules seems to have touched a few nerves. Perhaps I should explain my terms, since ugliness is surely in the eye of the beholder. I'm not talking about particular functional groups as much as I'm talking about the whole package.
First off, a molecule that does what it's supposed to do in vivo is (by my definition) not truly ugly. The whole point of our job as medicinal chemists is to make active compounds - preferably with only the activity that we want - and if that's been accomplished there can be no arguing. Of course, "accomplished" has different meanings at different stages of development. Very roughly, the mileposts (for those of us in discovery research) are:
1. Hitting the target in vitro.
2. Showing selectivity in vitro.
3. Showing blood levels in vivo.
4. Showing activity in vivo.
5. No tox liabilities in vivo.
And these all have their gradations. My point is that if you've made it through these, at least to a reasonable extent, your molecule has already distinguished itself from the herd. The problem is that a lot of structures will fly through the first couple of levels (the in vitro ones), but have properties that will make it much harder for them to get the rest of the way. High molecular weight, notable lack of polarity (high logP), and notable lack of solubility are three of the most important warning signs, and those are what (to me) make an ugly molecule, not some particular functional group.
My belief is that, other things being equal, you should guard against making things that have trouble in these areas. You may well find yourself being forced (by the trends of your project) into one or more of them; that happens all the time, unfortunately. But you shouldn't go there if you don't have to. It's also true that there are molecules that have made it all the way through, that are out there on the market and still have these liabilities. But that shouldn't be taken as a sign that you should go the same route.
Ars longa, vita brevis. There's only so much time and so much money for a given project, and your time is best spent working in the space that has the best chance of delivering a drug. A 650 molecular weight compound with five trifluoromethyl groups is not inhabiting that space. It's not impossible that such a compound will make it, but I think we can all agree that its chances are lower compared to something smaller and less greasy. If the only thing you can get to work is a whopper like that, well, good luck to all concerned. But we have to depend on luck too much already in this business, and there's no reason to bring in more.
+ TrackBacks (0) | Category: Drug Development | Life in the Drug Labs | Pharmacokinetics
I've been involved in another outbreak of the perennial debate about what kinds of compounds medicinal chemists should be making. I can summarize the way this usually goes:
Chemist A: "Look at all these ugly molecules! Why can't we institute some sort of "No-Suzuki-Coupling" rule for two days out of every week or something? Failing that, why doesn't everyone at least try to make things that look better from the start?"
Chemist B: "Nice thought - but the most potent molecules tend to be on the uglier end of the spectrum. And once you've made a single-digit nanomolar compound for the first time in a new project, it's impossible to walk away from it. It's almost like you get to choose: good physical properties, or good activity and selectivity."
Chemist A: "Don't look in these places if you don't want to find what's there. I'm tired of people making big insoluble monster compounds "just for SAR purposes". Because then some of them hit, and you're stuck with 'em."
Chemist B: "But I can't go give a project update and say that we found the most potent compound ever, but we're not going to follow up on it. And then spend the rest of the time telling everyone that we made a whole bunch of compounds with great properties, but hey, they have no activity. That's not going to do me (or anyone else) any good, right?"
Chemist A: "That's why you don't make the uglies in the first place, so you don't get put in that bind. Of course, what everyone says to do is to take that potent ugly compound and make it better, now that you've found it. Problem is, most of the time the things you do to make it "better" start to kill the activity. We'd be better off with fewer hot compounds, as long as the ones we had were decent."
And so it goes. This same debate has gone on in my other workplaces, too, and I believe that it's a general one across the industrial labs. Who's winning the argument at your shop?
+ TrackBacks (0) | Category: Life in the Drug Labs
June 14, 2009
My Twitter account usually only gets my posts on this blog (the first 140 characters of them, that is). But those of you who follow me there have been flooded with updates of a very different kind for the last 24 hours or so. My Iranian-born wife and I have been watching the news carefully, as the Iranian election situation seems to be getting out of control. She's been translating Farsi-language updates, and I've been reposting them - there will probably be more of this over the next few days.
You can imagine where my sympathies lie, as a non-religious guy with libertarian leanings. Confusion and bad luck to the mullahs, to everyone who helped them steal this election, and to their henchmen beating members of the opposition in the streets. Freedom of speech, freedom of assembly, and freedom of electoral choice are easy to take for granted in some parts of the world, but none of them come easy.
And more to the usual subject of this blog: the Iranians have produced a lot of top-notch people in science, medicine, and engineering - I've seen and worked with many of them. But I'd love to be able to see what they could accomplish working from a free and stable country, and I hope I get the chance. We'll see.
If you're looking for news, #iranelection on Twitter is a firehouse of information, good and bad, and will lead you to plenty of other sites. The National Iranian American Council is an excellent source, and Andrew Sullivan is doing a fine job covering the situation, too.
+ TrackBacks (0) | Category: Blog Housekeeping | Current Events
June 12, 2009
Well, this doesn't look good for Lilly. A huge pile of court documents has been unsealed in the ongoing lawsuits about Zyprexa's off-label promotion. The company has already paid some serious fines, and is now fighting it out with insurance companies and other plaintiffs who are seeking to recover their costs. Several states are suing them as well; those cases are still on their way.
Bloomberg News was given a lengthy list of internal company statements that will surely be difficult to explain in court. These were provided by one of the plaintiff's attorneys, Hagens Berman Sobol Shapiro LLP, so it's hardly a neutral selection (as Lilly is saying in response). But it's going to be interesting to see what sorts of explanations the company has for these. On the one hand, you have this:
In 1998, Lilly went back to the FDA seeking approval to market Zyprexa to those battling Alzheimer’s, the most common form of dementia, the company said in its 2003 request for a meeting on a proposed label change. Lilly withdrew its bid to promote Zyprexa for Alzheimer’s cases in 1999, according to the document.
In a November 2000 memo to Lilly salespeople, company executives said the dementia marketing initiative was abandoned because the FDA questioned Zyprexa’s effectiveness in treating the ailment.
“It was withdrawn due to vagueness on the FDA’s part regarding a definition of efficacy,” Lilly officials said in the document.
In a 2003 memo to FDA regulators citing the clinical studies, Lilly researchers acknowledged the death rates among older dementia patients on Zyprexa in the reviews were two times higher than their counterparts taking placebos.
Deaths among the patients taking Zyprexa in the studies were “significantly greater than placebo-treated patients (3.5 percent v. 1.5 percent, respectively),” Lilly officials said, according to the unsealed documents.
The studies didn’t find Zyprexa was effective in treating dementia, the company acknowledged in this document.
Lilly recognized this earlier, according to a 2002 document entitled “Zyprexa in serious mental illness (65 plus years) -- A Strategy Review.”
“The treatment of serious mental illness for people over the age of 65 has been identified as a growing opportunity for Zyprexa,” the authors wrote. “Unfortunately, attempts to gain the data to support an application for an indication in the treatment of dementia have to date been unsuccessful.”
But on the other hand, we have:
Lilly’s long-term care unit also saw Zyprexa sales rise 2.9 percent in the second quarter of 2002 as sales of Risperdal, Johnson & Johnson’s rival antipsychotic, fell, according to the 2002 marketing plan.
At that time, long-term care sales made up about 20 percent of Zyprexa prescriptions, according to the summary. Of that number, 65 percent were written for nursing-home patients.
Overall, prescriptions for older patients were the “2nd biggest money-producing segment” for Zyprexa in the U.S., according to a Feb. 15, 2002, e-mail from Lilly researcher Peter Feldman to Denice Torres, the company’s global marketing director.
In that e-mail, Feldman said company officials were saying in internal memos that they were going to stop studying Zyprexa’s potential health benefits for elderly consumers.
That would risk “killing the goose that lays the golden eggs to save on poultry feed costs,” Feldman said in the unsealed messages.
Torres assured him older consumers would continue to be a prime target for Zyprexa sales, according to the e-mail.
“Elderly remains an important aspect of target PT and affiliate focus,” she said in the message.
Increased Zyprexa sales to elderly patients also won Lilly’s long-term care unit praise in a 2003 newsletter unsealed as part of the documents.
“For two consecutive years, you have been on top and have turned in above-plan performance,” Grady Grant, Lilly’s national sales director, wrote in the newsletter. “I look forward to working with you as we set our sights on overtaking Risperdal as the number one antipsychotic in the marketplace!”
Lilly says these are cherry-picked quotes taken out of context. I'll await seeing what context they can be put in that will make them look less like. . .what they look like now.
+ TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System | The Dark Side
I spoke here about Scigen, the program that'll concoct a load of total nonsense for you and make it look - from a distance - like a journal paper. It's a surprisingly valuable tool, since the scientific publishing world apparently has a bigger demand for total nonsense than you might think, especially after the checks clear.
The latest example of this comes from The Scholarly Kitchen, where Philip Davis generated "Deconstructing Access Points", a paper that's nothing but a string of gibberish and non sequitars from first to last. It's here (in PDF form) if you want to try reading it. You won't get far; no human could.
Ah, but what if no human bothered to? That's what happened when Davis submitted this compost pile to the Open Information Science Journal, which is one of the new Bentham "open access" journals. You see, Bentham (like some other publishing houses) has heard that this open access stuff is like, the new trend, so they've started a line of their own journals. Once your paper's accepted, anyone can access it. Of course, there is a fee up front - to be fair, there pretty much has to be, if someone is actually going to do the back-end reviewing and editing work of a real journal. But what if you don't do any of that, and just charge the fee anyway?
Yes, the paper was accepted - of course it was accepted. It was accepted despite it being an unreadable mass of pseudo-English, and despite the fact that it was sent in under the banner of the Center for Research in Applied Phrenology. (Nice touch!) Here's the acceptance letter from an assistant manager at Bentham. All Davis had to do was send $800 to a tax-free zone in the United Arab Emirates and this manuscript would be inflicted on the world.
He pulled back at this juncture, but the point had been made. As he puts it, in milder tones than I would have: ". . .it does raise the question of whether, at least in some cases, the producer-pays-to-publish model may unduly influence editorial decision-making." Indeed it does, especially with a lower-tier publisher. Too much of the scholarly publishing world is involved in this sort of thing (and too much of the conference-organizing world, too, for that matter). I know that it's hard for many people to realize this, but it really is better not to publish at all than to abet this sort of thing.
+ TrackBacks (0) | Category: The Dark Side | The Scientific Literature
June 11, 2009
My recent entries in this category have, for the most part, been hazardous in a direct (not to say crude, or even vulgar) manner. These are compounds that explode with bizarre violence even in laughably small amounts, leaving ruined equipment and shattered nerves in their wake. No, I will not work with such.
But today's compound makes no noise and leaves no wreckage. It merely stinks. But it does so relentlessly and unbearably. It makes innocent downwind pedestrians stagger, clutch their stomachs, and flee in terror. It reeks to a degree that makes people suspect evil supernatural forces. It is thioacetone.
Or something close to it, anyway. All we know for sure is that thioacetone doesn't like to exist as a free compound - it's usually tied up in a cyclic thioketal trimer, when it's around at all. Attempts to crack this to thioacetone monomer itself have been made - ah, but that's when people start diving out of windows and vomiting into wastebaskets, so the quality of the data starts to deteriorate. No one's quite sure what the actual odorant is (perhaps the gem-dimercaptan?) And no one seems to have much desire to find out, either.
There are sound historical reasons for this reluctance. The canonical example (Chemische Berichte 1889, 2593) is the early work in the German city of Freiburg in 1889 (see page 4 of this textbook), which quotes the first-hand report. This reaction produced"an offensive smell which spread rapidly over a great area of the town causing fainting, vomiting and a panic evacuation.". An 1890 report from the Whitehall Soap Works in Leeds refers to the odor as "fearful", and if you could smell anything through the ambient conditions in a Leeds soap factory in 1890, it must have been.
The compound shows up sporadically in the literature until the mid-1960s, when several groups looked into thioketones as sources of new polymers. The most in-depth analysis took place at the Esso Research Station in Abingdon, UK, where Victor Burnop and Kenneth Latham got to experience the Freiburg Horror for themselves:
"Recently we found ourselves with an odour problem beyond our worst expectations. During early experiments, a stopper jumped from a bottle of residues, and, although replaced at once, resulted in an immediate complaint of nausea and sickness from colleagues working in a building two hundred yards away. Two of our chemists who had done no more than investigate the cracking of minute amounts of trithioacetone found themselves the object of