Corante

About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily

In the Pipeline

Monthly Archives

June 30, 2009

Voluntary, You Say?

Email This Entry

Posted by Derek

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.

Comments (28) + TrackBacks (0) | Category: Business and Markets

Devils, Metals, and Details

Email This Entry

Posted by Derek

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.

Comments (16) + TrackBacks (0) | Category: Chemical News

June 29, 2009

Eli Lilly Gives It Away

Email This Entry

Posted by Derek

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.

Comments (18) + TrackBacks (0) | Category: Drug Assays | Drug Development

June 26, 2009

Snort Yourself Some Zinc. Or Maybe Not.

Email This Entry

Posted by Derek

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.

Comments (143) + TrackBacks (0) | Category: Regulatory Affairs | Snake Oil

June 25, 2009

What's With Those People at Elsevier, Anyway?

Email This Entry

Posted by Derek

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.

Comments (13) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 24, 2009

Meanwhile, Over At Sanofi-Aventis. . .

Email This Entry

Posted by Derek

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. . .

Comments (9) + TrackBacks (0) | Category: Business and Markets

GSK's Getting Better. Just Ask the CEO.

Email This Entry

Posted by Derek

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. . .

Comments (19) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

June 23, 2009

Proxy Server Update

Email This Entry

Posted by Derek

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.

Comments (4) + TrackBacks (0) | Category: Blog Housekeeping | Current Events

Medarex, Ipilimumab, Prostate Cancer, And Reality

Email This Entry

Posted by Derek

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.

Comments (34) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | Toxicology

One. . .Billion. . .Dollars!

Email This Entry

Posted by Derek

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. . .

Comments (5) + TrackBacks (0) | Category: Business and Markets | Drug Development

June 22, 2009

Funky Carbocycles

Email This Entry

Posted by Derek

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?

Comments (5) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs

Genzyme's Virus Problems

Email This Entry

Posted by Derek

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.

Comments (21) + TrackBacks (0) | Category: Biological News | Drug Development

June 19, 2009

Proxies and Politics Again

Email This Entry

Posted by Derek

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?"

Comments (4) + TrackBacks (0) | Category: Current Events

More Hot Air From Me on Screening

Email This Entry

Posted by Derek

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.

Comments (25) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development

June 18, 2009

Professors Patent Pathways and Possibly Profit? Please.

Email This Entry

Posted by Derek

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. . .

Comments (23) + TrackBacks (0) | Category: Patents and IP

June 17, 2009

Politics: Proxy Servers Revisited

Email This Entry

Posted by Derek

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.

Comments (7) + TrackBacks (0) | Category: Current Events

The View From Pfizer's Corner Offices

Email This Entry

Posted by Derek

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.

Comments (37) + TrackBacks (0) | Category: Drug Development | Drug Industry History

June 16, 2009

Proxies for Iran (More Politics - Mixed With Technology)

Email This Entry

Posted by Derek

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!

Comments (20) + TrackBacks (0) | Category: Blog Housekeeping | Current Events

June 15, 2009

Ugliness Defined

Email This Entry

Posted by Derek

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.

Comments (13) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs | Pharmacokinetics

Don't Make Them in the First Place?

Email This Entry

Posted by Derek

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?

Comments (22) + TrackBacks (0) | Category: Life in the Drug Labs

June 14, 2009

And Now Some Politics

Email This Entry

Posted by Derek

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.

Comments (16) + TrackBacks (0) | Category: Blog Housekeeping | Current Events

June 12, 2009

Selling Zyprexa

Email This Entry

Posted by Derek

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.

Comments (19) + TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System | The Dark Side

Another Sack of Raving Nonsense Is Slated For Publication

Email This Entry

Posted by Derek

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.

Comments (17) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 11, 2009

Things I Won't Work WIth: Thioacetone

Email This Entry

Posted by Derek

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 hostile stares in a restaurant and suffered the humiliation of having a waitress spray the area around them with a deodorant. The odours defied the expected effects of dilution since workers in the laboratory did not find the odours intolerable ... and genuinely denied responsibility since they were working in closed systems. To convince them otherwise, they were dispersed with other observers around the laboratory, at distances up to a quarter of a mile, and one drop of either acetone gem-dithiol or the mother liquors from crude trithioacetone crystallisations were placed on a watch glass in a fume cupboard. The odour was detected downwind in seconds."

Now that's a compound to be taken seriously. How do you work with something that smells like hell's dumpster? Like this:

"The offensive odors released by cracking trithioacetone to prepare linear poly(thioacetone) are confined and eliminated by working in a large glove box with an alkaline permanganate seal, decontaminating all apparatus with alkaline permanganate, eliminating obnoxious vapors with nitrous fumes generated by a few grams of Cu in HNO3, and destroying all residues by running them into the center of a wood fire in a brazier."

So there you have it - just install a fireplace next to your hood (what every lab needs, for sure) and remember that, in a thioacetone situation, fogging the area with brown nitrogen oxide fumes will actually improve the air. (This is from Chemistry and Industry, 1967, p. 1430, if you need more details, and I hope you don't).

Comments (44) + TrackBacks (0) | Category: Things I Won't Work With

June 10, 2009

Word For Word - But Why?

Email This Entry

Posted by Derek

I missed this a couple of months ago, but there was a paper withdrawn from the Journal of Organic Chemistry. The original is here, a contribution from the Indian Institute of Chemical Technology in Hyderabad on 2-aryl benzothiazoles.

The JOC editor's note is here, and states:

This manuscript was withdrawn from publication by the Editor-in-Chief of The Journal of Organic Chemistry. The basis for the withdrawal was a violation of the Ethical Guidelines to Publication of Chemical Research of the American Chemical Society. . .

The reason given is plagiarism from a paper in Angewandte Chemie in 2008, which is from Carsten Bolm's lab in Aachen on S-arylation of thiols. And here we find the trouble. Below are two sections - the first from the JOC paper, and the second from the original Ang. Chem.:

Among the various intramolecular reactions, S-arylation is comparatively less studied.(14) Two factors make this process difficult: First, thiols are prone to undergo oxidative S−S coupling reactions which result in the undesired formation of disulfides, and second, organic sulfur compounds can be effective metal binders, which leads to catalytic modification (or deactivation).(15) However, given the prevalence of C−S bonds in a wide range of pharmaceutically active compounds and polymeric materials,(16) it is desirable to find novel procedures that provide efficient access to such highly useful organic products.


Among the various cross-coupling types, S-arylation is comparatively less studied.[3] Two factors make this process difficult: First, thiols are prone to undergo oxidative SS coupling reactions, which result in the undesired formation of disulfides, and second, organic sulfur compounds can be effective metal binders, which leads to catalyst modification (or deactivation).[4] However, given the prevalence of CS bonds in a wide range of pharmaceutically active compounds and polymeric materials,[5] it is desirable to find novel catalytic procedures that provide efficient access to such highly useful organic products.

There's no doubt that this is a copy-and-paste job. And I believe that the ACS policy cited doesn't leave much wiggle room - if you do this, you get slapped down. What's silly about it is that it didn't have to happen. People borrow such background material all the time, to greater or lesser extents. But word for word? Bad idea. Frankly, if the Hyderabad authors had spent twenty minutes rewriting those sentences, no one would have ever noticed a thing. The automated similarity searches that can be done now (which I presume led to this incident) would have passed right over.

But (as far as I know) the conclusions of the JOC paper are still valid. And if you care about 2-arylbenzothiazoles, you might even want to see them. I note that the paper is still on the JOC web site, even though it's been "withdrawn". Is this the middle ground, then, a way to discipline people without yanking the results completely from the literature?

Comments (31) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

Random Questions, Answered Randomly

Email This Entry

Posted by Derek

I had some requests to answer my own "Random Questions" from the other day, so here goes:

1. Does it bother you, or by contrast make you a bit proud, when you tell someone that you're a chemist and (as happens in about seven out of ten cases) they say "Oh, that was my hardest/least favorite/most boring subject when I was in school"?

Well, whether it bothers me or not, this happens all the time. Like pretty much every chemist in the world, I get to hear all about how people couldn't stand my subject in school. I take the point that mathematicians have it even worse, but it's not like we miss many of them with chemistry, either.

When people ask me what I do, I tell them "drug discovery", and I mention the diseases that I'm working on. That never fails to get some interest, and only then I spring on my listener the (often unexpected) info that this involves chemistry. Coming at it from that angle almost always leads to a good conversation, while coming at it from the "I'm a chemist" angle often leads to "Hey, look at the time!" effects. It's worth doing it in the right order, though - I like the effect when of showing that this boring/hard/useless subject actually leads to what most people find is a really interesting job.


2. How many thousands (10s, 100s of thousands) of dollars of unused equipment is sitting in dusty, unused storerooms at your company, because someone ordered it years ago and either (1) never got it to work, (2) was the only person ever to get it to work, or (3) found that it worked, but what it did wasn't worth doing that way?

Disused equipment? What is this disused equipment you speak of? Never have I seen such a thing. Why, those elaborate combichem machines in the sub-basement, they're just down there because they're so valuable. That rotating split-and-mix thingamabob and the multichannel parallel doohickey, we guard those closely.

Hah! Actually, I remember a couple of labs where this stuff wasn't in the basement at all. No, it was out there in the hoods, taking up space and slowly gathering dust, a standing reproach to everyone who walked past it. It would have been better off out of sight, but no one quite had the heart. And besides, it would sometimes get turned on for visiting groups - there was that.

3. Have you ever set up a reaction and thought "Boy, I sure hope that this doesn't work"?

I suppose that this is somewhat shameful, but yes, I have set up reactions hoping that they would fail. Usually it's been when I've had to use a particularly distasteful reagent (sodium ethanethiolate, for example), and I don't want to end up using it on a larger scale. I remember a fellow grad student presenting his work while we were trying to get our PhDs, and he detailed a deoxygenation step which only worked when his intermediate was made using a hefty excess of thiophosgene. "As fate would have it", said his long-suffering labmate from the back of the room.

And I've had less honorable instances, dating back to grad school or early in my industry career, when I was more or less forced to run a reaction a particular way even though I felt there was no chance for it to work. So yeah, in those cases I did look forward to saying "Yes, I tried your idea. And no, it didn't work any better than mine."

4. For the drug discovery people out there, what per cent of compounds you've made over the years would you guess dissolve in plain water to any real extent? Is that figure going up, or down?

The figure is hard to estimate, but it sure isn't high. Things that dissolve in straight water are hard to work with, y'know - they tend not to extract so well into ethyl acetate or dichloromethane, and they don't run so great on silica when you try to clean them up. That's worth another blog post in itself - the way that our standard chemistry techniques tend to push us away from a lot of polar molecules that might be just what we need for med-chem.

5. What, off the top of your head, would you say in retrospect is the most time-wasting chemistry you've ever ended up doing?

Tough competition. I'm tempted to say vacuum pyrolysis of corn starch to make levoglucosan, but I needed that for my dissertation, so it can't be called useless.

The real winner, in retrospect, has to be a series of reactions I did in my first couple of months in my grad school group, when I was still taking classes and working in the lab part time. I was presented with a route to a tetrahydropyran compound that we needed, a four-or-five stepper that involved an aluminum alkyne opening an epoxide, a Lindlar hydrogenation, a ring closure. . .I can still draw the damn thing on the board, now that I think about it, and it's been twenty-five years ago this spring. Being a first-year grad student, I hopped to it - and hopped right into the mud, since the route bogged down (and how) at the ring closure stage). I kept at it for a while, and then one evening I decided to look up my target compound in Chemical Abstracts.

That wasn't so easy in those stone ax and bearskin days - command-line access to CAS via a rockin' 1200 baud modem and a terminal was still a few months away. I paged through the five-year indices, and found. . .my compound. In a Tetrahedron paper. Two steps, from stuff you could buy from Aldrich, and you form the ring in the first step through a Prins reaction. I was shocked. Surely this couldn't be a known compound. Surely someone must have looked the structure up before coming up with that route I'd been given.

Surely not. And thus did my lab education begin. So you know, when I think about it, even though those first couple of months were a waste of chemicals and effort, perhaps they weren't as much a waste of time as I thought. . .

Comments (19) + TrackBacks (0) | Category: Graduate School | Life in the Drug Labs

June 9, 2009

Instant Med-Chem Wisdom

Email This Entry

Posted by Derek

I didn't note it here when it came out last year, but I wanted to recommend this paper to all the readers who are medicinal chemists. It's an effort by M. Paul Gleeson of GSK to generalize some rules from huge piles of oral dosing data in the company's files. It's all boiled down to a set of charts, for different classes of compounds (neutral, acidic, basic, and zwitterionic), and you can see the effects of changing molecular weight and/or polarity on things like bioavailibility, potential for hERG problems, clearance, etc.

There are no major surprises in the charts. But it's very useful to have all these "rules of thumb" in one spot, and to have them backed up by plenty of data. For experienced medicinal chemists, it's a distillation of everything that we should have been learning. And for those starting out, it's a way to get a fast understanding of what matters when you're making new structures. Check it out!

Update: for a much more sceptical take, see here.

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

Avastin's Numbers

Email This Entry

Posted by Derek

Here's a fascinating (and alarming) look at the clinical data from the recent trial of Avastin (bevacizumab) in adjuvant colorectal cancer (that is, post-surgical therapy). This was an issue in the recent Roche/Genentech takeover, since it could significantly enlarge the market for the drug. According to the In Vivo Blog, the one-year interim look at the data (adding Avastin to the standard chemotherapy regimen) was nearly good enough to stop the trial early. There were 2,710 patients enrolled, and an additional six events would have pushed things over the top, statistically.

The trial went on, though, with two more years of standard therapy as follow-up. But by the (pre-set) three-year endpoint it turned out that there was no eventual real benefit to adding Avastin back in that first year. So what's the story? Is it that you need to keep giving the combination regime? Would those-one year results have held up? Or is this just a case of real long-term survival numbers wiping out what seems to be a promising short-term result?

It looks like Genentech may be gearing up to put that first theory to a test, and I wish them luck. Long-term tolerability will be an issue, and long-term cost will be a big one, too. They're going to have to show some pretty impressive numbers to overcome those two concerns. . .as impressive as, well, as those first-year interim ones they had. Will that effect dissipate or not?

Time and money will answer that little question. But for now, consider what would have happened if a few more patients had shown disease-free survival in time for that interim analysis. The trial would have been stopped early, all kinds of people would have gone on Avastin for their first year of adjuvant therapy. . .and this year we would have seen that it was apparently doing no good at all, at least in the take-it-for-a-year-and-stop mode. Clinical trial design: a real high-wire act.

Comments (9) + TrackBacks (0) | Category: Cancer | Clinical Trials

June 8, 2009

Quick Blogroll Update

Email This Entry

Posted by Derek

In an effort never to let the blogroll slip like I did throughout 2007-2008, here are a few more chemistry/science blogs. Welcome to Zusammen, Chemical Crosspatch, Culture of Chemistry, and Chemical Professionals. As always, suggestions for new inclusions are welcome!

Update: Drug Discovery Opinion, too!

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

Rolofylline Hits the Skids

Email This Entry

Posted by Derek

There is no good way to spin a Phase III failure. By then you've made it past the main reasons for a drug to wipe out (PK and total mechanistic failure). A breakdown at this stage is a more subtle affair (well, except for the money involved, which is not subtle at all). For example, a drug might show efficacy in a carefully constructed Phase II trial, but can't perform under the wider (and more realistic) conditions of Phase III.

That's what appears to have happened to Merck's MK-7418 (rolofylline, formerly KW-3902). This adenosine A1 antagonist, which Merck picked up by buying NovaCardia a couple of years ago, was being developed for acute heart failure. That's a tough indication, and this isn't going to improve that reputation. (This Forbes piece has a tour of the pile of discards that this area has become over the years. Rolofylline looked as if it might work in Phase II, but (from what I can tell from the press releases) missed every endpoint in Phase III.

On a chemical note, rolofylline is a rather odd-looking molecule. You don't see many noradamantanes hanging off of drug structures. I'm sure this wasn't the reason for the compound's failure (after all, it made it through Phase I and Phase II), but it's sure not something I have on my list of structural fragments to try.

Comments (14) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

June 5, 2009

Live-Blogging A Conference: Trouble?

Email This Entry

Posted by Derek

There’s a report over at Genetic Future of some problems stemming from blogging a scientific meeting at Cold Spring Harbor. The organizers have a rule that reporters have to obtain permission from speakers before writing up a story on any given presentation, but no one thought about whether this covered bloggers. This caused a dispute between the blog's owner, the conference organizers, and Genomeweb about what was going on, and whose rules applied to whom.

This is a particular case of the larger blogs-versus-journalism question. I think it’s being resolved the right way: Cold Spring Harbor Labs will apply the same rules to people blogging, tweeting, or what have you as apply to people writing up stories for more conventional outlets. That makes sense to me, because in each case, there's a report for public consumption on what’s being presented. What sort of medium it appears on (newsprint, glossy paper, or pixels) shouldn’t matter. Neither, actually, should the issue of whether the piece will earn the writer any money or whether that's the writer's full-time job.

In any of these cases, the writer has an obligation to present an accurate report, of course. That’s one factor where science journalism (be it amateur or pro) has a potential edge on, say, politics. In the end, science isn’t (or shouldn’t be) so much a matter of opinion, of who yells the loudest or who has the most persuasive speaking style. The ideas and the data should speak for themselves, and conference reporting should, ideally, help them to do so.

I think that conference organizers should first be aware that people could be live-blogging. But after that, I think that they should be encouraging it. Information, as they say, wants to be free. And scientific meetings are one of the ways that it takes wing.

Comments (5) + TrackBacks (0) | Category: Press Coverage

Blog Contestification

Email This Entry

Posted by Derek

Voting ends Monday at the 3Quarks science blogging contest, so anyone who hasn't put their chip in can do so over the weekend. They're trying to make sure that everyone only votes once, which is a good plan. Looks like I have an entry or two doing well, and I've learned about several other blogs that I hadn't heard of before by looking over the tallies so far. Another blogroll update is pending!

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

June 4, 2009

Perpetual Patents: A Nasty Thought Occurs

Email This Entry

Posted by Derek

A colleague of mine read the "Perpetual Patent" item below, and had a thought of his own. "If I were the head of a company that just discovered something like Lipitor", he said, using the example that the Xconomy piece used as well, "I'm probably going to fire all the early stage research people. Who needs 'em? We've got a never-ending patent on a huge drug".

And you know, I hate to say it, but I can't completely rule that one out myself. Not every management team would do this, but some would indeed transform the place from "Company That Looks For New Drugs" to "Company That Found One And Will Now Live Off It For As Long As Possible". After all, the R&D part of the operation is, most of the time, a huge drag on the bottom line. You only keep it around because you need it to come up with something that'll bring in the revenue eventually. So what happens if you decide that your current level of revenue is pretty good - and would look even better if you got rid of that big cost center?

Comments (18) + TrackBacks (0) | Category: Business and Markets | Patents and IP | The Dark Side

CafePharma Will Now Approach The Bench

Email This Entry

Posted by Derek

Here's an interesting situation for you: according to IguanaBio, a shareholder lawsuit over the failed Vytorin ENHANCE clinical trial (that's caused Schering-Plough and Merck so much grief) is going to use posts on CafePharma as evidence.

That will be worth watching. CafePharma's message boards have been described (accurately, I'd say) as often being the electronic equivalent of a bathroom wall. There's good information in there, but the signal/noise ratio is abysmal due to the number of ticked-off people who go there to vent. There do appear to have been some posts suggesting strongly that the ENHANCE data were grim, and who knows? They could have been speaking from real knowledge. But there's no way to be sure - and for every post that turns out to be prophetic, there are ten that are totally wrong.

So I'm surprised that these are going to be considered admissable. Anyone investing on the basis of CafePharma board chatter deserves to lose their money - which will go out in brokerage commission fees, if nothing else. Let's see how this plays in court. . .

Comments (8) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Industry History

Perpetual Patent Motion Machine

Email This Entry

Posted by Derek

Over at Xconomy, there’s a provocative piece entitled “Diamonds Are Forever: Why Not Drug Patents?”. You have to give the author (Carl Weissman) credit for not playing to the crowd, I guess. So what’s his reasoning?

I can own a tangible good forever, I can own a trademark virtually forever, I can own a copyright for my entire life plus 70 years. But property which is more intrinsically a part of me - my idea, my invention, the product of my intellect - I am only allowed to own that for 20 years after I reveal it to the patent office.

Rationally, it seems obvious that all property - whether tangible or intellectual - should be subject to the same rules and laws of ownership. If you can own a gemstone forever, you should be able to own an invention forever. In fact, if a society wishes to impose differential standards for ownership rights to different types of property, wouldn’t it make more sense that preferential treatment be given to those items which are the product of your talent, your creativity, your self, over those things which you earn or purchase based upon that product of your efforts? The logical extension of this argument, in any free society, is that you should be able to own all property, whether purchased or invented, physical or ethereal, for as long as you wish. Patents, trademarks, copyrights, title - all should be perpetual.

Of course, since patents and copyright aren’t perpetual, someone must, along the way, have made a case for why they shouldn’t be. I’m going to stick with patents in this post, since copyright isn’t nearly as relevant to the drug business, but I refer you to this discussion and the links therein for some reasons why copyright is probably too lengthy in the US already. (A quick note: no creative work has gone into the public domain in this country since 1978. This is a state of affairs we can blame partly on a cartoon mouse, which also benefits some guys in capes).

The idea behind a patent system is that you will disclose your idea, in enough detail that others can follow it and build on it. In return, you will get a licensed monopoly on it for a set period of time, after which it becomes available to all, to profit from as best they can. We can argue about how well this ideal is realized – how full the disclosures are, how long the rights should last (and how long they really do). But I think that the basic idea is a sound one.

But Weissman just brushes it off, as far as I can see. His piece addresses some of the possible objections, but mostly by assertion. He points out that me-too drug efforts manage to populate therapeutic spaces (such as with the statins), and says that this shows that no monopolies would be created by perpetual drug patent rights. But any analysis of the drug landscape has to take into account that it came about under the current patent system. Everyone knows that Lipitor, for example, is going to expire eventually, and that their own drugs will, too. And everyone has planned accordingly. It’s not possible to draw conclusions about a perpetual patent regime by bringing up examples from the current one, since it’s so different. It’s only possible to draw these conclusions from the inner recesses of one’s own body – the brain, of course I mean.

His next point is drug pricing:

”With a perpetual patent, drug companies would be free to think longer term about pricing (without the artificial addition of patent lifetime in the equation). They would set prices lower in order to discourage new competitors from entering their market. This would enable the innovator to retain greater market share, and generate higher long term sales. The likely result is pricing near, if not lower, than current generic pricing.”

I’m not necessarily buying this one, either, since I think that drug companies will, like anyone else, try to maximize profits. And I think that the ability of (somewhat) lower prices to discourage competition is low, compared to the lure of more immediate higher profits. But really, drug pricing isn’t my biggest concern with this whole idea. That comes up here:

”In fact, with perpetual patents, the public good is better served because the incentive to discover and develop drugs is maximized. Secure in the knowledge that they will own the products of their own discovery and development efforts, drug companies will be able to assess the true risk vs. reward of any development programs free of artificial time limits imposed upon their ownership of those products.

Now here’s where I really part company with this idea, once and for all. I see where he gets this idea – patent rights are the incentive for discovery, so stronger patent rights are an incentive for even more discovery, right? But that first sentence is almost totally wrong; let me see if I can spell out why. No, what keeps us discovering new drugs is the fact that our patents are going to expire.

There, that wasn’t hard. But it’s true. The time limits we work under are one of the things that keeps everyone moving. We work hard before filing, because we’re afraid that someone else will scoop us. And we work hard after filing, because the clock has begun to tick. Every patent is a wasting asset, which is what seems to be driving Weissman crazy. And sometimes it drives me crazy, too, but I think his solution is even crazier.

I’m not arguing for shortening patent terms, either, just in case someone gets that idea. There’s a range where companies have the best chances to realize the return on their ideas and their labor, and I’m not sure that we’ve quite found it. But I know for sure that the patent lifespan needed is somewhere between zero and infinity. And I know that the argument for infinity does not convince. Just because a time limit is artificial doesn't mean it's wrong, or that there should be no time limit at all.

Comments (34) + TrackBacks (0) | Category: Patents and IP

June 3, 2009

Will The Gentleman With the Pitchfork Please Speak Up?

Email This Entry

Posted by Derek

A few blocks from where I'm sitting, Biogen is having its shareholders meeting today. And since Carl Icahn is still trying very hard to gain leverage in the company's board, it seems to be turning into quite a spectacle over there. (More details).

They're supposed to reconvene at 2 PM for more voting. But from the sound of it, people are adjourning to go out and buy machetes and tire irons. We'll how things come out. . .

Comments (8) + TrackBacks (0) | Category: Business and Markets | Current Events

Random Questions

Email This Entry

Posted by Derek

Not much time for a post this morning, so I'll throw out a few questions for the readership. Feel free to answer any, all, or none:

1. Does it bother you, or by contrast make you a bit proud, when you tell someone that you're a chemist and (as happens in about seven out of ten cases) they say "Oh, that was my hardest/least favorite/most boring subject when I was in school"?

2. How many thousands (10s, 100s of thousands) of dollars of unused equipment is sitting in dusty, unused storerooms at your company, because someone ordered it years ago and either (1) never got it to work, (2) was the only person ever to get it to work, or (3) found that it worked, but what it did wasn't worth doing that way?

3. Have you ever set up a reaction and thought "Boy, I sure hope that this doesn't work"?

4. For the drug discovery people out there, what per cent of compounds you've made over the years would you guess dissolve in plain water to any real extent? Is that figure going up, or down?

5. What, off the top of your head, would you say in retrospect is the most time-wasting chemistry you've ever ended up doing?

Comments (37) + TrackBacks (0) | Category:

June 2, 2009

Blog Contestiness

Email This Entry

Posted by Derek

Voting has started on that 3Quarks science blog prize - here's the voting page. I have several posts on their nominees list, so I'll probably be diluted a bit, but please vote for your favorites (and discover some blogs that you probably haven't heard about).

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

A Deuterium Deal

Email This Entry

Posted by Derek

Well, there's someone who certainly believes in the deuterated-drug idea! GlaxoSmithKline has announced today that they've signed a deal with Concert Pharmaceuticals to develop these. There's a $35 million payment upfront, which I'm sure will be welcome in this climate, and various milestone and royalty arrangements from there on out. I know that the press story says that it's a "potential billion dollar deal", but you have to make a useless number of assumptions to arrive at that figure. Let's just say that the amount will be somewhere between that billion-dollar figure and. . .well, the $35 million that Glaxo's just put up.

Where things will eventually land inside that rather wide range is impossible to say. No one's taken such a compound all the way through development, and every one of them is going to be different. (Deuterium might be a good idea, but it ain't magic.) It looks like the first compound up for evaluation will be an HIV protease inhibitor, CTP-518, which is a deuterated version of someone's existing compound - Concert has filed paten applications on deuterated versions of both darunavir (WO2009055006) and atazanavir (WO2008156632). The hope is that CTP-518 will have an improved enough metabolic profile to eliminate the need to add ritonavir into the drug cocktail.

The company is also providing deuterated versions of three of GSK's own pipeline compounds for evaluation, which is interesting, since that's the sort of thing that Glaxo could do itself. In fact, that's one of the key points to the whole deuterated-compound idea: the window of opportunity. Deuteration isn't difficult chemistry, and the applications for it in improving PK and tox profiles are pretty obvious (see below). It's a good bet that drug company patent applications will hencrforth include claims (and exemplified compounds) to make sure that deuterated versions of drug candidates can't be poached away by someone else. This strategy has a limited shelf life, but it's long enough to be potentially very profitable indeed.

One more note about that word "obvious". Now that people are raising all kinds of money and interest with the idea, sure, it looks obvious. And I'm sure that it's a thought that many people have had before - and then said "Nah, that's too funny-sounding. Might not work. And besides, you might not be able to patent it. And besides, if it were that good an idea, someone else would have already done it. There must be a good reason why no one's done it, you know". Getting up the nerve to try these things, that's the hard part. Roger Tung and Concert (and the other players in this field) deserve congratulations for not being afraid of the obvious.

Comments (25) + TrackBacks (0) | Category: Business and Markets | Drug Development | Infectious Diseases | Pharmacokinetics | Who Discovers and Why

June 1, 2009

Akt and Mek, But Not PDQ

Email This Entry

Posted by Derek

Well, the ASCO meeting has been roaring along, with dozens of press releases coming out. (Go to Google News and type that acronym in if you want to get the full experience). They range from the pretty-interesting to the despair-inducing, but one bit of news struck me as particularly worth noting. That's the early-stage deal between Merck and AstraZeneca to combine two of their development candidates in a Phase I trial.

That's Merck's AKT inhibitor MK-2206 and AZ's Mek inhibitor AZD6244, and there's room to think that combining those two mechanisms could be beneficial. But as that In Vivo Blog link details, this deal wasn't initiated through any official contact between the two companies. Rather, someone from Merck and someone from AZ got to talking while they were going through airport security in Dublin, and recognized each other's names. A mere year and a half later, the deal was born.

There's a lot to learn from that story. For one, big drug companies are not, for the most part, looking to do early-stage deals with other big drug companies. Perhaps we'll see more of these in the future, but in general, it's about the least likely form of partnership. Another thing to note is how long it took for this idea to bear fruit. Eighteen months is about right for companies of this size to make up their minds about something like this - and you can decide that (since the oncology field is so complicated) that this is a reasonable period of evaluation, or you can decide, equally objectively, that delays of that magnitude remind you of a sauropod turning around in puzzlement three hours after something bit its tail.

I'm impressed that the deal was made at all. The usual path for new ideas of this sort is to the graveyard, especially in very large organizations, so I have to assume that some people within each company must have really pushed things along to make it happen. It's part of the general bias toward inaction: it's harder to get beaten up for decisions that you didn't make, compared to decisions that you did. Missed opportunities are often invisible.

So, no matter how long it took, or even whether it works out, I still have to congratulate the people involved on getting this agreement to happen. It's worthwhile, I think, just because it's the sort of thing that doesn't happen very often. And I have the feeling that (in the coming years) we're going to have to explore a lot of things in this industry that haven't happened very often. We'll need the practice!

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development | Drug Industry History