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Home > Weblog Columns > In the PipelineWeblog columns [select a blog][Corante Blog]BETWEENLAWYERS: technology + culture + lawBRAINWAVES:neurons, bits & genesCOPYFIGHT: thepolitics of intellectual propertyGOYAMI: search engine marketingIDEAFLOW:creativity+ innovationIN THEPIPELINE: drugdiscoveryMANY-TO-MANY: socialsoftwareREBUILDINGMEDIA: the economics of mediaSTRANGE ATTRACTOR:social mediaTOTALEXPERIENCE: experience designAbout this Author 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.comChemistry and Pharma Blogs:PharmalotOrg Prep DailyOn PharmaOne in Ten ThousandAway From the BenchQDIS BlogChemical MusingsIn Vivo BlogThe ChemblogMolecule of the DayKinase ProDrugs and PoisonsJungfreudlichChembarkSocial DetritusPharmagossipWhistling in the WindOrganometallic CurrentGreat Molecular CrapshootPost Doc Ergo Propter DocA Chemist's Lab NotebookThe Curious Wavefunction
January 8, 2009Short Items: India, Sanjay Gupta, Satori Pharmaceuticals Posted by DerekI have a few short links for everyone today. One series of posts that you might not have seen from Xconomy is a tour of the technological hot spots of India by Boston University's Vinit Nijhawan. It's interesting stuff for people like me who haven't been to the country, and he isn't shy about pointing out both the good and the bad about India's current situation. He's not focusing on the chemistry/pharmaceutical sector, but it's an interesting read in general. I would very much enjoy seeing a similar series written from China - perhaps the Xconomy folks are working on that one?Next: if Sanjay Gupta really is going to be surgeon general (and why not?), it's worth watching his exchange with Michael Moore when Moore's movie "Sicko" came out. This is a 17-minute YouTube clip, and you may not make it through if you can't stand Michael Moore, but it has some good moments. Gupta is a *lot* more reasonable dealing the Moore than I would have been, but gets hammered on for his pains anyway.And here's an interesting one, from a financial standpoint. Raising money for startup companies has, in the last few months, gone from the usual state of “not so easy” to “nearly impossible”. Everyone’s hoping for that to improve, but for now, this is a nasty time to try to float a new startup. That goes for follow-on financing, too, naturally, and that can hurt even more than troubles with start-up money. You can potentially delay the launch of your new venture – after all, no one else is getting anything off the ground, either – but if you’re already got a company going, the funds need to keep flowing. Companies that lined up more money in the middle of 2007 are shivering over the narrowness of their escape.So it's impressive that an outfit called Satori Pharmaceuticals has made it through a full round of venture funding, and for Alzheimer's therapies, no less. That's a notorious graveyard for good ideas, but (at the same time) it's equally notorious for being hugely under-served. Good luck to them - they'll need it (and don't we all?)Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Current Events | Press Coverage January 7, 2009Things I Won't Work With: Azidotetrazolate SaltsPosted by DerekAn early favorite has appeared in my “most alarming chemical papers” file for this year. Thomas Klapoetke and Joerg Stierstorfer from Munich have published one with a simple title that might not sound unusual to people outside the field, but has made every chemist I’ve shown it to point like a bird dog: “The CN7 Anion”. The reason that one gets our attention is that compounds with lots of nitrogens in them – more specifically, compounds with a high percentage of nitrogen by weight – are a spirited bunch. They hear the distant call of the wild, and they know that with just one leap of the fence they can fly free as molecules of nitrogen gas. And that’s never an orderly process. If my presumably distant cousin Nick Lowe does indeed love the sound of breaking glass, then these are his kinds of compounds. A more accurate song title for these latest creations would be “I Love the Sound Of Shrapnel Bouncing Off My Welder’s Mask”, but that sort of breaks up the rhythm.These Bavarian rowdies have prepared a series of salts of the unnerving azidotetrazolate anion. As they point out, the anion was described back in 1939 (in what I hope was a coincidental association with the outbreak of the Second World War), but its salts are “rarely described in the literature”. Yes indeed! People rarely spray hungry mountain lions with Worcestershire sauce, either, come to think of it.After reading this paper, I’m considering taking my chances with the mountain lions. The authors report a whole series of salts, X-ray structures and all, which range from the “relatively stable” lithium and sodium derivatives all the way to things that couldn’t even be isolated. In the latter category is the rubidium salt, which they tried to prepare several times. In every case, the solution detonated spontaneously on standing. And by “spontaneously”, they mean “while standing undisturbed in the dark”, so there’s really just no way to deal with this stuff. It’s probably a good thing they didn’t get crystals, because someone would have tried to isolate the hideous things. The cesium salt actually did give a few crystals, which they managed to pluck from the top of the solution and get X-ray data on. A few hours later the remaining batch suddenly exploded, though, which certainly must have been food for thought.The authors went on to investigate the thermal behavior of these wonderful compounds, another risky move. As it turns out, they have calorimetry data on only five of the salts, because when they got to the sodium derivative, “a violent explosion destroyed the setup”. They also did sensitivity tests, using a standard drophammer rig from the Bundesanstalt fuer Materialforschung, evocatively abbreviated as BAM. These, along with the friction and spark tests, put these compounds well into the “primary explosive” category. Well, the ones that they could get data on, that is: the potassium and cesium compounds blew up as they tried to get them into the testing apparatus. So it’s safe to assume that they’re a bit touchy, too.One of my favorite parts of the paper is the mention (found in much of the recent high-energy materials literature) that high-nitrogen compounds are worth investigated as “green” explosives, which makes me think that the whole environmental-rationale business must be reaching its end points. The notion of a more environmentally friendly way to blow things up aside, I have to salute the paper’s authors. They’ve made compounds that no one will have to make again, and survived the experience. Read the paper and be glad that this wasn’t your PhD project. . .Comments (17) + TrackBacks (0) | Category: Things I Won't Work With New ChemistryPosted by DerekSo I see that Nature Chemistry looks to be fueling up to launch. I’m curious to see how that one will do. The other Nature journals have done pretty well at preserving the prestige of the name, but I hope that they haven’t reached the point of diminishing returns just when they get to my specialty.And this will be unusual, since you don’t see many attempts to launch a high-end journal from scratch. Most new journals aim for the middle (or worse), figuring that that’s where the papers will come from. But Nature Chemistry will presumably try to compete with JACS and Angewandte Chemie. My guess is that they’ll be able to do that, which means that the journals one tier down will be the ones that feel the consequences. On the other hand, it’s not like Nature has a reputation for paying much attention to chemistry over the years, so perhaps the cachet won’t carry over in the same way that it did for, say, Nature Medicine. We shall see. . .Comments (2) + TrackBacks (0) | Category: The Scientific Literature January 6, 2009Why Pfizer?Posted by DerekI get occasional comments and e-mails asking why I’m so hard on Pfizer. It’s not that I have anything personal against the company – I’ve never worked there, and they’ve never turned me down for a job. And I have a lot of friends there as well - the company has a lot of good people working for it. No, it’s not Pfizer so much as the way that Pfizer exemplifies for me a lot of things that I think have gone wrong with the industry.First, of course, is sheer size. As I’ve said numerous times, I think that many things scale as a drug company gets larger, but research productivity isn’t one of them. If anything, it may go in the other direction. Pfizer is an excellent example of just what I’m talking about. If there were any reliable correlation of size to internal research success, this is where you’d expect to see it. But Pfizer has been notoriously unproductive in its own labs. Some of that has been sheer bad luck, but you can’t use that explanation to cover the whole problem.Put simply, I think that really huge drug companies are a bad thing. A collection of smaller ones carved out of the same resources would probably explore more therapeutic avenues, and in a more nimble and focused manner. I also like competition in this business, because it keeps us moving, and because it leads to a wider variety of approaches being tried out for each problem. Mergers and buyouts have, I feel sure, not been good for the ecology of the industry, and Pfizer is the absolute champion of that style. Large and productive research organizations have disappeared beneath the waves because they had the misfortune of discovering something that Pfizer wanted to buy.And there’s also the triumph of marketing. That’s one area where Pfizer really excels, but the problem with being a marketing powerhouse is that you might end up thinking that you can sell almost anything. The company’s disastrous experience with Exubera (the inhaled insulin product that missed its sales targets by, what, 98 per cent?) is a sobering example. If you start believing your own press releases, you might convince yourself that you’re going to sell a billion dollars of Exubera, and at a huge company you’ve got the money and the resources to pursue that dream right over the cliff. Groupthink finds a bigger arena in which to work its magic.So there it is. Other companies have similar problems, but when you go to Pfizer, you find them all together, in concentrated form. So when they announce that they’re going to go out and buy someone else to work their way out of their (massive) coming troubles, it makes me wince. It just seems like the opposite of what we need.Comments (28) + TrackBacks (0) | Category: Business and Markets | Drug Industry History Pharmalot Is No MorePosted by DerekI noted with sadness yesterday that Ed Silverman has packed in the Pharmalot blog. He did an excellent job there, picking up a lot of industry news from all over. Most of it was in the “Trouble for Company X” vein, but that’s to be expected. Ed’s a good reporter, and “Things Going Fine Over at Company X” is not much of a story. If this item is correct, though, we’ll be seeing more of him, which I’m glad to hear. The newspaper business is in even worse shape than the drug industry, so I’m glad to see it when someone there lands safely. (People still need pharmaceuticals; they’re not so sure if they need newspapers so much). Comments (4) + TrackBacks (0) | Category: Press Coverage January 5, 2009Well, Hose Me Down. . .Posted by DerekPfizer's Jeff Kindler says that the company: "is willing to acquire a large rival drug company to improve its financial health".In other news, bears have expressed a willingness to defecate in forested areas.Comments (20) + TrackBacks (0) | Category: Current Events New Year - I Hope!Posted by DerekIn past years, around this time I’ve often done a look back at the previous year in the drug industry. I hope that no one will be disappointed if I scuttle that tradition, because honestly, I have no desire whatsoever to relive what drug research went through in 2008. It may have been the toughest year for industry scientists in the modern era – everyone I know struggles to find a comparison.I’d rather spend my energies on 2009. Let’s just stipulate that 2008 was, on balance, horrendous: what does that tell us? How did we end up in this position, and how can we avoid more of the same? There’s a lot of arguing room in those questions, but I think that we can agree that the proximate cause is that we’re not coming up with enough good drugs. 2008, for all its ugliness, was a handful of good products away from being a decent year. Why were we short that handful?You have to go back some years to answer a question like that, given the industry’s lead time. The projects that were begun in the mid-to-late 1990s are clearly not coming through in the way that everyone had hoped. Is it that our attrition rate has gone up, or have we just not taken enough things to the clinic, or some of each?Let’s think about that first problem, which certainly seems to be real enough. Is it that the easy targets have all been worked over, leaving us with only the tough ones? I don’t think that’s the whole explanation, although that’s certainly part of it. Still, even some of the big drugs from years past wouldn’t have made it through our current structures. So are the hurdles set too high during development – that is, do we know too much about potential problems, without having learned a corresponding amount about how to fix them? That’s got to be a big factor, which leads to a New Year’s resolution: try to spend as much time fixing problems as finding them. That’s a hard one to live up to, but it’s a goal to work toward.And if we’re going to talk about that latter number, we’re going to have to cut through the often artificial “projects advanced” figures that circulate inside companies. Anyone who’s been around this business has seen some long shots (and some outright losers) officially pushed forward just to make some year-end target. Now, long shots are fine. To a good approximation, everything we do is a long shot. And everything has to go to the clinic eventually (or die) – but we have to make sure that we’re not just checking boxes. So that’s another resolution: spend less time kidding ourselves.Of course, there’s a flip side to the number of compounds going to the clinic. Could it be that we’re being too cautious, because we have too many potential worries (those high hurdles mentioned above)? Should we be taking more things forward? Well, that’s an expensive proposition, the way things are set up now. So here’s another hard-to-live-up-to resolution: find ways to go to the clinic without betting our shirts every time. That’s been a big focus the last few years (biomarkers, etc.), but we need every idea and technique we can think of (microdosing? Simulations, even?). The cost of getting answers in humans is getting too high for us to try out as many ideas as we need to.And here's a less macro-scale resolution, which I plan to start putting into practice immediately: don't let fear run your research. Try some things that you aren't sure about. Take some chances. Put down some bets. I've got several that I've let sit in the should-I-do-this limbo for too long, and I'm going to do something about that. Join me?Comments (12) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Who Discovers and Why December 23, 2008Holiday BreakPosted by DerekPosting will be intermittent around here until after January 1st. I'm going to be doing various important tasks at home, such as wrapping presents and making another chocolate pecan pie for folks who didn't get any the last time around. There's also some snow to be shoveled, particularly if I want to get the telescope out during this period of new moon. There's 15 to 20 inches out there on the ground, which is not much of a stable surface for the equatorial platform to sit on, nor do I relish wading through it while hauling the telescope tube itself.My workplace is very quiet indeed today, I can report, and later on I'll be doing my part to keep it that way. I suspect it's the same across a lot of labs today and for the next few days, and that's a good thing. It's impossible to have good ideas when you're grindstoning away the whole time; you need to clear your head every so often and take a look at what you're actually doing versus what you should be.This is one of the only times when sleeping late and eating pecan pie come under the heading of "clearing one's head", so I'm going to take full advantage of it. I hope that many of you can do the same!Comments (19) + TrackBacks (0) | Category: Blog Housekeeping December 22, 2008Publish Your Work The Easy WayPosted by DerekI say unkind things about various scientific journals here on occasion. But I have to say that I've never encountered a situation in chemistry that matches the affair of M. S. El Naschie, editor of the Elsevier journal Chaos, Solitons, and Fractals. It's nice to see the editor-in-chief show up with an occasional paper in his own journal - keeping one's hand in and all. But El Naschie has published three hundred and twenty-two papers in the journal since he assumed editorship. He has five in the December issue alone!The N-Category Cafe, a math blog from the University of Texas, has the full story here. Briefly, El Naschie seems to have been running this journal as his own private kingdom for some time now. While I'm not qualified to referee his works, those who are report that his papers don't make much sense - "undisciplined numerology larded with impressive buzzwords" is one review at the UT site. (That's a phrase I'm going to have to remember for future use; it's bound to come in handy).Would you like to subscribe to this fine journal, and get the latest updates from El Naschie-land? That'll run you $4520/year. As a library, you'll be getting that as part of a bundle of other presumably more useful journals, so you won't be paying full whack. But still. Why pay anything for a vanity press full of nonsense? (And if there are some real papers in there from other groups, then I pity them for having to appear alongside the gibberish).Elsevier seems to have finally caught on, after many recent protests. The journal's home page now states:The Founding Editor for Chaos, Solitons and Fractals Dr El Naschie will retire as Editor-in-Chief. This will be announced in the first issue of 2009.The publisher will work with the editorial board and other advisors to identify a new editor, as well as reviewing the aims and scope of the journal, as well as the editorial policies and submission arrangements. I'll bet they will. What's puzzling is why this took so long - isn't anyone at Elsevier paying attention? And why did it take some math bloggers to get things rolling - where has everyone else been in the field all this time? Just rolling their eyes and chucking the issues into the circular file, apparently. As I say, I don't know of anything close to this in chemistry - if anyone has info to the contrary, let's get on it ourselves. . .Comments (22) + TrackBacks (0) | Category: The Scientific Literature December 19, 2008My Compound Goes Where the Wild Goose GoesPosted by DerekA colleague and I got to talking yesterday about something that I'm sure many chemists have noticed. Have you ever chased down some reaction or compound in the literature, only to find yourself wild-goosing back to some obscure journal that no one has ever read - just because no one can be bothered to publish a modern procedure?Here's how that typically works. You run a SciFinder search on Molecular Structure X. A list with a dozen references comes up. There's a Tet. Lett. from 2002, but what are the chances it'll have any spectral data (or anything useful at all?) Ah, there's one from Tetrahedron in 1995, that should do. So you look over the PDF, search for your compound. . .there it is, number 17. Now to the experimental. . .and you find in the first paragraph that "Compound 17 was prepared according to a published procedure", footnote thirty-eight. And the footnote is to. . .ay, it's to a Chem. Ber. paper from 1932. Ausgezeichnet!Oh-kay. Back to that SciFinder reference list. How about that Tet. Lett. paper? Nope, on inspection, it turns out to reference the 1995 paper you just looked at. What else? There's a JOC from 1984, let's try that. Good ol' JOC, solid stuff. Well, digging up that PDF, you find that it refers to a 1980 paper from the same group from Synthesis. Hrm. So you chase that one down, there it is, compound 9, and the experimental for it is. . .footnoted to the 1932 paper. Again.And that's how it goes. Like as not, you can go through the whole list and find that it's made of tissue paper where your compound of interest is concerned. The whole presence of the compound in the literature is, in the end, based on some obscure German university's report from the last days of the Weimar Republic. What's irritating is that while those 1932 folks clearly must have made the compound, it's not always easy to get those papers immediately. And chemistry has, in fact, changed a bit since those days. Papers from that era rely on distillation and crystallization: there are no chromatographic purifications, because there was (by our standards) no such thing as chromatrography. Spectral data? Hah! UV/Vis was cutting edge back then. You'll get a melting point, an adjective-laden description of the appearance of the crystals, and maybe even a note about how the stuff tastes. Great.You know that the people who re-made the stuff during the last 25 years didn't steam-distill their product or fractionally crystallize it from some mixture of benzene and carbon disulfide or whatever. They ran a quick column and they took an NMR. So why can't they publish that data? The only reason I can usually see is laziness. Why bother? It's a known compound; just reference it and get that manuscript out the door. . .Comments (27) + TrackBacks (0) | Category: The Scientific Literature December 18, 2008When Placebos Were All There WerePosted by DerekYesterday's discussion of how to deal with various forms of pseudoscientific hoo-hah naturally brought up several mentions of the placebo effect. And that prompts me to bring in the late Lewis Thomas's The Youngest Science, his memoir of a life in medicine. We should never forget that there was a time, not all that long ago, when drug therapy was almost all placebos. Here's a description of the way Thomas's father practiced in the 1920s:Nevertheless, despite his skepticism, he carried his prescription pad everywhere and wrote voluminous prescriptions for all his patients. TThese were fantastic formulations, containing five or six vegetable ingredients, each one requiring careful measuring and weighing by the druggist, who pounded the powder, dissolved it in alcohol, and bottled it with a label giving only the patient's name, the date, and the instructions about dosage. The contents were a deep mystery, and intended to be a mystery. The prescriptions were always written in Latin, to heighten the mystery. The purpose of this kind of therapy was essentially reassurance. . .They were placebos, and they had been the principle mainstay of medicine, the sole technology, for so long a time - millennia - that they had the incantatory power of religious ritual. My father had little faith in the effectiveness of any of them, but he used them daily in practice. They were expected by his patients; a doctor who did not provide such prescriptions would soon have no practice at all. . .That's the world as it was. Thomas later recounts the profound shock he experienced as an intern when sulfanilamide was introduced: patients given up for dead got up out of their hospital beds and asked for something to eat. It was then, he says, that he realized that the medical profession he was entering might be turning into something different from what his father knew.We should never forget: it's our job to make our children look back on today's medicines with the same mixture of pity and alarm. To cure disease, stop the damage, make people given up for dead stand up and walk out of the room to see their families. Things aren't going very well for us now in this business, because these are all very hard things to do, and the amount of time and money needed to do them is nearly unbearable. But not quite. We can see that such things are possible, and it's up to us to figure out how to make them real. Comments (17) + TrackBacks (0) | Category: Drug Industry History December 17, 2008Awkward ConversationsPosted by DerekWe need a lighter topic today, and I’ve got one appropriate to the season, since many people will be having parties and family get-togethers over the next couple of weeks. And although some of these will be full of scientists, there are others where you might be the lone representative from the world of chemistry, biology, or medicine. That can be a good thing – or not so good, depending on how the conversation turns. A reader e-mailed me an account of a recent encounter with a relative who assured him of the benefits of foot-bath detoxification to cure what ails you. As you'd imagine, he didn't quite sign on to that idea, and the discussion went through a few rocky rapids.I know that this sort of thing has happened to me several times. I’ve had to deal with the topics of how no, it’s not a conspiracy of the drug companies to make vitamin-based therapies illegal – and how yes, I have been working for X number of years in the drug industry without discovering a single thing that’s on the market, and how that’s statistically rather likely. And I’ve explained how it’s hard to come up with a cure for Alzheimer’s when you don’t even know what causes Alzheimer’s, which argument generally meets with agreement. But that reasonable discussion gets canceled out by plenty of others.Dealing with the crazier propositions takes some real tact. I’m a pretty even-keeled guy, so I generally take a calm approach, just telling them how it is for me after X years of experience in the drug industry. I've found it's harder for people to spout craziness when there's some reasonable person sitting across the table from them who makes a living on the opposite side of their beliefs. And, truth be told, many of the wilder beliefs in the health field aren't necessarily all that strongly held. Most of them don't stand up to much scrutiny (and contradict each other, to boot), and I've found that people pick up and discard them with relative ease.But you do run into passionate believers now and then. I'd be interested in hearing from people how they've dealt with conversations like this. My usual progression goes something like:1. That's interesting - where did you hear about this?2. No, it's true, I really have been working on those diseases for years now. As far as I can tell, they're pretty hard to deal with.3. Gosh, that anecdotal evidence sure does sound convincing. Pity the FDA won't let us use any of that where I work. Those nutritional supplement manufacturers sure have it easy since the Hatch-Waxman act, don't they?4. Hmm, since Fact X seems to be true about Disease Y, based on all that I know about the subject, how do these fit together?5. Well, you know, the laws of physics/chemistry/math that I learned don't seem to cover that particular effect - have they added some recently?5. No, I think that if there were any conspiracy that big, I probably would have noticed it at some point. Unless you're suggesting that I'm part of the cover-up?6. Actually, people in the drug industry die from Disease Y, too. You'd think that if we were sitting on the cure for it, we'd have some sort of employee program or something. . .Comments (30) + TrackBacks (0) | Category: General Scientific News December 16, 2008Layoffs. More Layoffs.Posted by DerekI’m told by several people that today Bristol-Myers Squibb is announcing layoffs in research (and perhaps other areas). I don’t know how extensive these are, or how they’re spread across the New Jersey and Connecticut sites. What I do know is that accounting practices make these things especially rough, since a disproportionate number of such cuts take place before year’s end, which doesn’t do much for anyone’s holiday season. (Of course, I suppose it could be even worse – you could be working for Pfizer, and spend the holidays not knowing if your job was going to be there in January or not). In a smaller but deeper cutback, I also note that Entremed, a company that’s been struggling to survive ever since its turn in the spotlight with Judah Folkman’s anti-angiogenic peptides, has announced that sixty per cent of its employees will be let go. Since that includes the CEO and CFO, you have to conclude that the situation there is not good.Having been through the layoff process myself, I know what the people involved are going through, and I wish them every hope of landing new positions. If anyone out there knows of companies that are hiring now in research, or even planning to, I’d be glad to list such in a separate post in order to provide some leads.One other related item: I’ve heard from Linda Raber at C&E News who’s working on a "Careers in Pharma" story for them, and wants to write about all the chemistry layoffs this year. She’d like to hear from people who are willing to be quoted on what things have been like. (Update: you don't have to be identified - see the comments section for contact info!) I was quoted in a similar story after the Wonder Drug Factory layoffs, actually; this sort of piece is turning into more of a perennial than anyone would like.Comments (53) + TrackBacks (0) | Category: Business and Markets | Current Events December 15, 2008Insider Trading in Drug Stocks? Not Unknown. . .Posted by DerekWith all the financial scandals going on these days (really, a multibillion-dollar Ponzi scheme run by the former head of NASDAQ?), it’s worth asking how often such shady dealing goes on with the stocks of drug companies. From what I can see, it does happen, but it’s certainly not endemic.The first thing that comes to mind is insider trading. Since many companies see their stock move abruptly on the single news items pertaining to clinical trials results, regulatory actions, adverse events, and so on, front-running is always going to be a problem. And I’m sure that it goes on, but I also know that companies put a lot of effort into trying to keep it from happening. For clinical trial results, that means that such information is strictly need-to-know, and believe me, not that many people need to know. Most companies have a rather short list of people who see such numbers before a public release, which makes tracking down suspicious trades a bit too easy for comfort, if you’re inclined to reach for the easy money. I’m certainly not on any such list myself, and never have been.There are other kinds of material information, but it’s still rare for anything that goes on in my end of the industry to affect the stock price. We’re just too far from the clinic and from the FDA to make that much of a difference. But in any case, I agree with a definition of “material information” that I once heard: if it makes you think about trading the company’s stock, and it’s not in a press release already, it’s material information. And you act on it at your peril.But that doesn’t mean that people don’t act. Sam Waksal of Imclone is merely the most famous executive to place a phone call to his broker at an inopportune time. The chief legal counsel over at Biogen Idec got in hot water a couple of years ago about a suspicious options trade around the time of the bad news about the company’s Tysabri. (The case was settled with the SEC, with no language about wrongdoing involved - there was still some reasonable doubt about the timing of the trade, although it would have been far more prudent to not have made it). A few years before that, the chief attorney at Vertex got into trouble with another ill-advised trade of his own company's stock. And there are others, naturally.Then there's the problem with theoretically-embargoed information from the big clinical meetings like ASCO. In recent years, it's become clear that this stuff is leaking out in one form or another, because interesting trading patterns become evident in the run-up to the meetings themselves. I think that sending out an abstract book while trying to keep the lid on them is probably futile. Of course, in many cases the real stock-moving news in such cases doesn't come from anything in the abstract book, but from the information in the presentations themselves, which is all later-breaking stuff added long after the abstract submission deadline. So you could argue that people trading on the pre-meeting stuff are still kidding themselves. . .The closest I've ever come to this sort of thing myself was some years ago. A colleague attending a clinically-oriented meeting in a particular medical specialty called some of us back at our company to say that an anticipated series of posters and talks from another company didn't look like it was going to materialize. No one from that organization was putting anything up for the poster session. We guessed that there was some last-minute problem with their compound - and so it proved in a press release the next morning.It occurred to me during that afternoon that a stock or options trade could well be profitable, but I didn't go through with it. It would have been profitable (especially the options, naturally), but in the end I didn't quite have the nerve. I still don't think that it would have been illegal, but I didn't like the idea of explaining actions of mine in those terms. "Not illegal as far as I know" isn't exactly the rock on which one wishes to make one's stand, you know?Comments (9) + TrackBacks (0) | Category: Business and Markets | The Dark Side December 12, 2008The Worst Biotech CEO?Posted by DerekI'm pleased to note that Adam Feuerstein over at TheStreet.com has announced his first-ever "Worst Biotech CEO" award. In what was surely a contested field, he's named Elan's Kelly Martin as the winner. I was pulling for Ariad's Harvey Berger, who seems to have come close. Well, there's always next year - and yes, I do need to update the Ariad story soon.Martin's win is a result of the troubles with the anti-Alzheimer's antibody bapineuzumab this year. When pivotal trial results came out back in July, they weren't too exciting. Investors, though, had been very excited indeed, and Elan's stock took a terrible beating as a result. According to Feuerstein, Martin's cheerleading for the drug was the reason for this unprofitable disconnect from reality.He certainly wouldn't be the first CEO to beat the drum for his company's drug, but this kind of thing has a big risk of backfiring. How do investors believe you after they've been burned in this fashion? You don't want to have to depend on fresh crops of people who haven't heard your story yet. Alzheimer's is a tremendously difficult field to make headway in, and everyone who wants to buy into something in it needs to understand that. As an investment, such drugs are worth taking a flier on, but with a clear understanding that the odds are long. I think that Elan (and their partner, Wyeth) deserve credit for going after something as unusual as an immune-based therapy for the disease, but there's no excuse for making people think that it's working if it really isn't. Anyway, be sure to check out Feuerstein's take, along with the comments on Vanda, Medarex, and other favorites. I hope he keeps this up year after year: there will never be any shortage of contenders.Comments (7) + TrackBacks (0) | Category: Business and Markets December 11, 2008Pfizer's Restructuring Grinds AlongPosted by DerekSo, Pfizer: it seems as if they’ve been going on about cutting their research staff for months now. Well, its has been months, and the whole thing is turning into a rather bitter joke for people in Groton, from what I can tell. This current wave of restructuring has been rumbling along since back in the summer, and they told people about the layoffs in the fall. How long is all this going to take?The latest announcement from the higher layers is that the company will announce its plans “sometime in January”. Lee Howard, a reporter at the New London paper The Day, has a copy of a letter from Pfizer’s Rod MacKenzie (head of discovery research worldwide) to employees, saying that because the changes in research are so complex, he won’t be able to communicate them by the end of the year. I’m not sure if the letter includes his greetings for a Merry Christmas and a Happy New Year; maybe that one will arrive in time for Valentine’s Day. Here's the article, the comments to which erupt in a lot of vituperative town-vs-gown New London crossfire.From what I’m hearing, the coming changes are going to be quite profound in chemistry. Pfizer seems to be dividing its chemists up into people who think up molecules, and people who make them, with no real overlap. You’re probably thinking sure, that’s how the Germans and the Swiss tend to do it, the PhDs in the offices and the BS/MS folks out at the hood. But apparently there are PhDs on the “make the molecules” side in Pfizer’s new scheme, although I think the “design the molecules” side will have no one who isn’t. At any rate, the traditional medicinal chemist, someone who has an idea for a new molecule and then goes out to the lab and makes it, will seemingly have no place at Pfizer. You do one, or you do the other.And I’ve heard from several sources that major outsourcing will be a big part of the new system as well. The “drug designers” will also be resource managers, spending their time figuring out what compounds and series to ship over to China, and what to have the local groups work on. As readers here well know, I think that outsourcing definitely has its place, but Pfizer seems to be going even further down that road than the rest of the industry – how well that’s going to work is an open question. A lot of the outsourcing work I’ve seen over the years has been. . .OK. Used judiciously, that’s fine, but I don’t know if I’d want to base whole programs on it if I didn’t have to.I think it’s safe to say that morale and productivity in the labs in Groton must be drooping a bit these days. How could it not be, with everyone waiting for months to see who’s going to be let go, and in this economic climate? I understand that it’s a big organization, and that figuring out what to do is a complicated job. I certainly wouldn’t want it. But the way this is being done has not reflected well on the company’s management and how it treats its employees. But we’ll just have to add this one to the existing lists in both categories. . .Comments (57) + TrackBacks (0) | Category: Business and Markets | Current Events December 10, 2008Floppiness Is Not Your Friend: Who Knew?Posted by DerekThere’s a trick that every medicinal chemist learns very early, and continues to apply every time its feasible: take two parts of your compound, and tie them together into a ring.The reason that works so well may not be immediately obvious if you’re not a medicinal chemist, so let me expand on them a bit. The first thing to know is that this method tends to work either really well or not at all – it’s a “death or glory” move. And that gives you a clue as to what’s going on. The idea is that the rotatable bonds in your molecule are, under normal conditions, doing just that: rotating. Any molecule the size of a normal drug has all kinds of possible shapes and rotational isomers, and room temperature is an energetic enough environment to populate a lot of them.But there’s only one of them that’s the best for fitting into your drug target, most likely. So what are the odds? As your molecule approaches its binding pocket, there’s a complicated energetic dance going on. Different parts of your drug candidate will start interacting with the target (usually a protein), and that starts to tie down all that floppy rotation. The question is, does the gain resulting from these interactions cancel out the energetic price that has to be paid for them? Is there a pathway that leads to a favorable tight-binding situation, or is your molecule going to approach, flop around a bit, and dance away?Several things are at work during that shall-we-dance period. The different conformations of your compound vary in energy, depending on how much its parts are starting to bang into each other, and how much you’re asking the bonds to twist around. The closer that desired drug-binding shape is to the shape your molecule wants to be in anyway, the better off you are, from that perspective. So tying back the molecule and making a ring in the structure does one thing immediately: it cuts down on the range of conformations it can take, in the same way that tying a rope between your ankles cuts down on your ability to dance. You’ve handcuffed your molecule, which would probably be cruel if they were sentient, but then, a lot of organic chemistry would be pretty unspeakable if molecules had feelings.That’s why this method tends to be either a big winner or a big loser. If the preferred binding mode of your compound is close to the shape it takes when you tie it down, then you’ve suddenly zeroed in on just the thing you want, and the binding affinity is going to take a big leap. But if it’s not, well, you’ve now probably made it impossible for the thing to adopt the conformation it needs, and the binding affinity is going to take a big leap over a cliff.There’s another effect to reducing the flexibility of your compound, and that has to do with entropy. All that favorable-interaction business is one component of the energy involved, namely the enthalpy, but entropy is the other. Loosely speaking, the more disordered a system, the higher its entropy. A floppy molecule, when it binds to a drug target, has to settle down into a much tighter fit, and entropically, that’s unfavorable. Energetically, you’re paying to do that. But if your molecule is already much less flexible, there’s not much of a toll as it fits into the pocket. If loss-of-floppiness is a bad thing, then don’t start out with so much of it.So, how much do I and my medicinal chemistry colleagues think about this stuff, day to day? A fair amount, but there are parts of it that we probably don’t pay enough attention to. Entropy gets less respect from us than it deserves, I think. It’s easy to imagine molecules bumping into each other, sticking and unsticking, but the more nebulous change-in-disorder part of the equation is just as important. And it doesn’t just apply to our drug molecules – proteins get less disordered as they bind those molecules (or more disordered, in some cases), and those entropic changes can mean a lot, too.I also mentioned molecules finding a pathway to binding, and that’s something that we don’t think about as much, either. We probably make things all the time that would be potent binders, if they just could get past some energetic hump and wedge themselves into place. But there are no crowbars available; our drug candidates have to be able to work their way in on their own. The can’t-get-there-from-here cases come back from the assays as inactive. The tendency is to imagine these in the binding site already, and to try to think of what could be going wrong in there – but it may be that they’d be fine, but that their structures won’t allow them to come in for a landing.Picturing this accurately is very hard indeed. We have enough trouble with good representations of static pictures of our molecules bound to their targets, so making a movie of the process is a whole different story. Each frame is on a femtosecond scale – molecules flip around rather quickly – and every frame would have to be computed accurately (drug structure, protein structure, and the energetics of the whole system) for the resulting video clip to make sense. It’s been done, but not all that often, and we’re not good at it. Comments (13) + TrackBacks (0) | Category: In Silico | Pharma 101 December 9, 2008Goldman Sachs: A New Drug Research Model?Posted by DerekNow, here’s an odd item from the Financial Times (registration required): Goldman Sachs is in talks to provide hundreds of millions of dollars of funding to a large pharmaceutical company, in the first evidence of a new business model for the sector that will see financing shifted away from funding companies and towards targeted co-development of specific medicines. . .. . .(The model involves) a different approach, creating a "research pool" into which pharma companies would place a range of experimental drugs in a single therapeutic area in early-stage phase 1 and 2 trials, where their specialists would work alongside external experts including scientists, chemists and clinical research organizations.This was announced at a conference run by the newspaper, so they’re really the only source for information on this. I haven’t been able to find anything from Goldman about it, for example, and the minimal press coverage so far has all pointed back to this article. (Ed Silverman picked it up at Pharmalot, for example).So one wonders what’s up, because the information that’s given raises more questions than it answers. I presume that the assumption is that since only a few early-stage clinical compounds ever make it, that this gives everyone a chance to share the risk. But which therapeutic area are we talking about here? How are things apportioned when one compound makes it through? And what if more than one does? And where are these external experts coming from, and who pays them?This could be very interesting, because I think that we need to be open to some new research models in the industry. The current one isn’t exactly spewing results these days. But I wish that I knew more about what this proposal involves – anyone out there have any more details that they can share?Comments (8) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development December 8, 2008Enhancing the Brain: Here We GoPosted by DerekDepending on what news sources you follow, you may have heard a lot about it already: taking cognition-enhancing drugs to improve normal brain function. An editorial in Nature has just come out in favor of it, so although I wrote about this back in April, it’s time to talk over the issue again.Let's define what we're talking about first. We really don’t have anything to selectively affect memory or general intelligence per se, but we do know something about how to affect attention span and wakefulness. So right now, cognition enhancement is mostly going to be found via the stimulants used for attention-deficit disorders, along with Cephalon’s Provigil (modafinil) for narcolepsy. These are the drugs of issue.Nature started off this latest debate on this a few months ago, when they took an informal survey to see how many scientists used these. The results came in as “more than you might think”, although still a decided minority. One got the impression that these were reached for during grant-writing time in academia, for the most part, which would make their usage pattern similar to what you’d find among the student population. My guess is that the number of people using these in industrial research would be far smaller, for several reasons. For one thing, our work moves in different rhythms. As opposed to academia, we rarely have situations where a Big Creative Work has to be produced (or a huge pile of facts memorized) under time pressure. We do have big reports and presentations that come due, of course, but by the time the big ones are due there have been a lot of smaller ones, and the slides and material are largely summaries of those. It’s not to say that many of us couldn’t benefit from some extra attention to our work, it’s just that the opportunities for such aid aren’t as clear-cut.Any discussion of this topic has to start with the question of how much good such drugs do. I’m willing to stipulate that for situations like the ones I’ve been describing – a need for long, sustained periods of focus and attention to detail – that these compounds do indeed help. They may be more beneficial for some people than for others, but yes, I think that their effect is real. (If anyone has evidence to the contrary, I’d be glad to hear it – I should also mention that I have no personal experience to draw on).And that brings up another question, the second big one that always comes up in such a discussion: is it right to do this sort of thing? Now that’s a tangle, because a value judgment has come into the room. And anyone who wants to take a hard line has to deal with the fact that we already have a legal, well-known, widely used drug for cognitive enhancement: caffeine. If that doesn’t increase wakefulness, I’d like to know what does.The comparison with steroid use in sports will also come up, although I regard that one as partially a red herring. The whole point of athletic competition is different from the point of achievement in the arts and sciences. All sports are essentially artificial constructs that we agree on rules for, and doping makes people worried and/or furious that these rules are being bent. Science, on the other hand, is the real world. If Barry Bonds did indeed break home run records with chemical aid – personally, I think he did – then a lot of people (including me) have a problem with that. But if someone comes up with, say, a proof of the Riemann Hypothesis with the use of modafinil and methylphenidate, well. . .a proof is a proof. But there is a competitive aspect that the sports analogy does bear on: several junior faculty may all be vying for tenure at the same time, for example. If they’re all roughly equal in ability, does the appointment end up going to the one who uses pharmacological help most effectively? That’s where the same uneasy feeling starts to set in. It’s when you look at head-to-head, human-to-human cases that the arguing really gets going.We’re going to have more and more of this to deal with in the future. I don’t expect it any time soon, but we’ll eventually be able to do more for memory – and, for all I know, for higher cognition. There are too many therapeutic reasons to investigate such things, and too many reasons for any useful drugs not to quickly escape to the population that doesn’t necessarily have anything wrong with it.All of these issues are addressed by the authors of the latest Nature commentary, naturally. For example:"Consider an examination that only a certain percentage can pass. It would seem unfair to allow some, but not all, students to use cognitive enhancements, akin to allowing some students taking a maths test to use a calculator while others must go without. (Mitigating such unfairness may raise issues of indirect coercion, as discussed above.) Of course, in some ways, this kind of unfairness already exists. Differences in education, including private tutoring, preparatory courses and other enriching experiences give some students an advantage over others.Whether the cognitive enhancement is substantially unfair may depend on its availability, and on the nature of its effects. Does it actually improve learning or does it just temporarily boost exam performance? In the latter case it would prevent a valid measure of the competency of the examinee and would therefore be unfair. But if it were to enhance long-term learning, we may be more willing to accept enhancement. After all, unlike athletic competitions, in many cases cognitive enhancements are not zero-sum games. Cognitive enhancement, unlike enhancement for sports competitions, could lead to substantive improvements in the world."The editorial comes down to several main points: that we need more solid data on the benefits and risks of such drugs for normal individuals, that competent adults should have to option to use them, and that policies should be worked out to deal with issues of fairness, coercion, and the like. My own thoughts on this are deeply confused and divided. That’s partly because I’m a weirdo: I don’t drink alcohol, and in fact, I don’t even drink coffee. That goes back to what I’d have to classify as a deep reluctance to mess with the way my brain works through chemical means, a trait that was already well in place by the time I was a teenager, but which was only reinforced as I learned more and more biochemistry. So on one level, I have to think that we really don’t know enough about how the existing cognitive enhancing drugs work, let alone what we’ll know about future ones, and that alone would keep me away from them.But I can come up with plenty of thought experiments that shake me up: imagine that the risks are better known, and that they're as much as, say, caffeine (but with more benefits). What then? What if such things turn out, many years in the future, to be necessary to work at any reasonably high level in science, since everyone else will be taking them, too? Is part of my problem with drugs that alter brain function a streak of Puritanism - would I feel better about using such things if I knew that they were guaranteed not to be enjoyable? And so on. . .I have to confess, I found such issues a lot easier to deal with inside the confines of old science fiction stories.Comments (19) + TrackBacks (0) | Category: General Scientific News | The Central Nervous System December 5, 2008Squinting At The Pictures, The Modern WayPosted by DerekFellow chemists, let’s address a housekeeping problem. I know that not all of us are thrilled at all times with the American Chemical Society, but I think that we can agree that the journals it runs are (for the most part) a valuable resource.And in these days of modern times, as the Firesign Theatre used to say, the presence of such journals on the internet is crucial. As many of you know, the ACS recently revamped the web pages for its journals, adding a number of new functions. Unfortunately, they seem to have taken away some at the same time.Initially, on too many of journal sites, the graphical abstract was presented at a default size of “itsy bitsy”. If you wanted to browse the ASAP in-press articles, you had to squint at tiny, fuzzy blobs to see what the authors of each article wanted you to know about it. And that’s clearly not what a graphical abstract is for, is it? I'm relieved to see that this seems to have improved in the last few days.But I'm not sure when the change took place, because I hardly ever visit the front doors of the ACS journals I read. That’s because I, like many other scientists, follow these things through RSS feeds. (I use Google Reader myself – if anyone’s just setting up an RSS reader and would like my OPML file, just e-mail me and I’ll send it along and save you some time).And what does the RSS feed look like now? Well, for several days, there were no graphical abstracts at all, which made the ACS feeds look just as ugly and nonfunctional as the Elsevier ones. Way to go! (Isn’t it odd that Tet Letters, the journal that pioneered the whole idea of a graphical abstract in chemistry, doesn’t include its graphics in its RSS stream? I don’t get any, at any rate). Which reminds me - if you don't care for the Wiley feeds, either, specifically Angewandte Chemie's, you can get a better version of that one here.I wrote the ACS support people and complained about the problem, and was told that they were fixing things. Well, their idea of a fix is apparently to include the tiny, blurry graphic in the feed – those have started showing up this week, and an irritatingly useless sight they are. This is one of those examples of taking something that was perfectly useful before – the RSS feeds they way they were last month – and improving them into junk. The ACS pages will be down again on Sunday, presumably for more fine-tuning. We'll see if the feeds return to functionality next week. If they don't. . .well, please consider adding your voice to the chorus asking that they do. Thanks!Comments (19) + TrackBacks (0) | Category: The Scientific Literature December 4, 2008Curse Of the Lost CompoundsPosted by DerekThere are some groups of compounds that seem to have a curse on them. They show up in drug screening, they have activity that’s often too good to ignore, but hardly anyone can manage to turn one of them into a drug.Trifluoromethyl ketones are one example of this. They’re classic inhibitors of proteases, especially serine proteases, and of other enzymes that depend on a serine in their active site. That’s because that ketone really isn’t much of a ketone – the fluorines make the carbon rather unhappy when it’s in that state, electron-poor and ready to pick up a nucleophile and go tetrahedral again. Trifluoromethyl ketones are generally seen in their hydrated state, unless you take care to dry them out, and they’ll work an active-site serine OH into their scheme as well. So you end up with a covalent inhibitor, but a reversible one – the activity comes on slowly, and the compound comes off slowly, too. That trick can work with cysteine nucleophiles, and the hydrate form is also known to coordinate with active-site zinc atoms – so it’s no surprise that the enzyme inhibition literature on these things is mighty extensive: proteases, lipases, esterases, deacetylases, the list goes on for a while.But although several of these have gone into the clinic over the years, I can’t think of one that’s make it all the way to the market (I’d be glad to hear of any that I’ve overlooked). The best guess is that this isn’t the fault of the functional group, but of the targets it’s been applied to. Some of these enzymes just haven’t panned out, so perhaps the trifluoromethyl ketone awaits its day in the sun.Another group of this sort is the hydroxamic acid. Its strength is its coordination to zinc atoms, so you see it all over the place in the metallaloprotease literature, and in other zinc-y fields like histone deacetylases. And in vitro, it hardly has a peer. I’ve seen list after list in the literature comparing various zinc-binding head groups, and likely as not, the hydroxamic acid sets the standard every time. But the reason you see those lists is that people are trying to find something that’ll work other than a hydroxamic acid. There are numerous complaints, ranging from “hydroxylamine is explosive on large scale, you know” and “they’re a pain to make reproducibly” through “they have ugly PK in the animal models” all the way up to “they’re toxic” and “how many of them have ever made it through the clinic?”. How much merit each of these have can be debated, but all together they make an unpleasant picture.In this case, though, I do know of one that’s made it - SAHA (Zolinza, vorinostat). That one came out of a long-term academic project involving Paul Marks at Sloan-Kettering and Ron Breslow's lab at Columbia, and is one of the not-so-numerous examples of drugs that have made it from the university to the marketplace. Merck signed up to do the clinical and regulatory lifting on this one, and it's now marketed for cutaneous T-cell lymphoma.So it is possible to get a hydroxamic acid through. "Well, yeah," say the voices, "for cancer, sure. Home of the world's only boronic acid-containing drug. Home, if you really want to get down to it, of nitrogen mustards and God knows what else. Cancer." And it's true that the standards are a bit more relaxed there. I wouldn't necessarily want to give someone a hydoxamic acid every day for the rest of their life, true - the things coordinate iron, for one thing, which isn't always good. But there are other fields where short-term therapy makes sense, and we probably haven't seen the last of this functional group, either.Comments (10) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History December 3, 2008Roche Stalls For TimePosted by DerekRemember back earlier this year, when the temperatures were high, the Dow was at 11,000, and Roche announced that they wanted to buy the rest of Genentech. So how’s that working out?Not all that well, as far as can be told from the outside. This would take around 45 billion dollars, and 45 billion dollars is a sum that’s increasingly hard to borrow these days. According to Reuters, the prospects for Roche putting together a syndicated loan for that amount are “becoming increasingly remote”. I can believe it. That would surely be the largest deal going at the moment, and given the state of the credit markets, the terms would probably curl your hair if they did manage to float such a beast. And who’s willing to, even if they have that kind of capital sitting around?For its part, Roche has been telling everyone that they’re still committed to buying Genentech, and that they’re completely confident of getting the financing together. Of course, they’ve been saying that since July, basically word for word, and as the months go on those repeated statements of confidence start to have the opposite effect. So if Roche really is committed and so on, what are they going to have to do?Reach in and dig out more equity and cash, most likely. What else? Apparently the company is trying to avoid doing that, and they’re willing to leave things hanging until the situation improves. But if you can predict when people are going to be in the mood to lend that kind of money, well, you should be out there making a fortune on the Street with such insights. (I would be!) And if anyone tells you that they have the macroeconomic situation figured out for the next few months, ask them if they went short on oil futures back in the summer. You’d think that anyone with any kind of magic touch would have known enough to do that.One consequence of all this is that people at Genentech have been living in a cloud of uncertainty for months now, and will stay there for the foreseeable future. That can’t be helping morale or productivity. And if there are any places for people to go, it’s also giving them plenty of time to find them. No, Roche’s timing, in retrospect, looks perfectly awful. When (and if) they finally get around to buying Genentech, what, exactly, will they have bought?Update: a Genentech VP says that all this has had no impact on morale, actually. You can take that as you wish. . .as for me, I'd find that extraordinary, if it were true.Comments (14) + TrackBacks (0) | Category: Business and Markets December 2, 2008Torcetrapib: What Was the Problem? And Does It Matter?Posted by DerekEver since the catastrophic failure of Pfizer's HDL-raising CETP inhibitor torcetrapib in late 2006, everyone involved has wondered just what the problem was. There was a definitely higher cardiovascular-linked death rate in the drug-treatment group as opposed to placebo - which led to the screeching halt in Phase III, as well it might - but why? Is there something unexpectedly bad about raising HDL? Or just in raising it by inhibiting the CETP enzyme, which might well provide a different lipoprotein profile than other high-HDL ideas? Was it perhaps an off-target effect of the drug that had nothing to do with its mechanism? And for any of these possibilities, is there the possibility of a biomarker that could warn of approaching trouble?There are now two analyses of clinical data that may shed some light on these questions (thanks to Heartwire for details and follow-up). The first, a new analysis from Holland of the RADIANCE trial data, shows an electrolyte imbalance (low potassium and higher sodium) in the treatment group. Measuring carotid wall thickness, they found no correlation between the degree of HDL elevation and progress of disease, which is disturbing. The only correlation was with lower LDL levels, and the authors point out that torcetrapib has unappreciated LDL-lowering activity. (Of course, there are easier and more proven ways to do that!)The second, the ultrasound-monitored trial called ILLUSTRATE led by the Cleveland Clinic, actually did show a correlation between HDL levels and disease progression, as measured by PAV (per cent atheroma volume). This paper concludes that the drug did perform mechanistically, but that needs some qualification. Overall, there was no real significant change in PAV, but looking more closely, the individual changes did seem to correlate with the amount of HDL elevation each group of patients achieved. Only the very highest-responding group showed any regression, though.Interestingly, this study also showed the same sort of electrolyte imbalance, and both teams seem to agree that torcetrapib is showing off-target mineralcorticoid effects. Steve Nissen of the Cleveland group is more optimistic (a phrase one doesn't get to write every day). He thinks that a CETP inhibitor that doesn't hit the adrenals might still find a place - but I have to say, looking over the data, that it sure won't be the place that the companies involved were hoping for. Instead of being world-conquering cardiovascular wonder drugs, perhaps the best this class of compounds can hope for is a niche, perhaps alongside statin therapy. I just don't see how this level of efficacy translates into something all that useful.But we'll see. Merck's anacetrapib is still going along. The data we have so far suggest that the compound raises HDL without effects on blood pressure, as opposed to torcetrapib. So maybe (for whatever reason - blind luck, I'd say) this compound doesn't do anything to the aldosterone pathway. But does it do anything to atherosclerosis? That's the question, and that's what the big money will have to be spent on in Phase III to find out. A comment at the Wall Street Journal's Helath Blog has it right:Welcome to the challenges of pharmaceutical research. Pharmacogenomic evidence originally led Pfizer to hope that elevating HDL through inhibiting CETP would be beneficial. A biomarker assessment in patients suggests that plaque reduction is associated with the highest HDL elevations. Yet, with torcetrapib, there appears to be a safety biomarker popping up. Are either the efficacy or safety signals really biomarkers of long term clinical outcome? You only need to ante up $800M to run mortality and morbidity trials for 5 or more years. Any investors?Comments (2) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology December 1, 2008Prodrugs: How the Pros Do It?Posted by DerekI’m going to write this morning about a question that actually came up among several of us at the train station this morning. I’m on a route that takes a lot of people into Cambridge, so we have a good proportion of pharma/biotech people on board. And today we got to talking about prodrugs: like 'em or hate 'em?For those not in the business, a prodrug is a masked form of an active drug, designed to be activated once it’s dosed. That’s generally done by allowing the normal metabolic processes of the body to clip some group off, revealing the real drug. Various esters are the most common prodrugs, since that’s about the easiest group to have fall apart on you. (Enalapril / enalaprilat is a classic example, and aspirin is an even more classic one).And esters illustrate another point about prodrugs: no one develops them unless they have to, as far as I’m concerned. After all, if your compound works fine in its native form, why get fancy? No, I think you turn to the prodrug strategy when there’s something wrong. Maybe the active form of the drug isn’t well absorbed from the gut, or has too short a half-life in the blood, or doesn’t distribute to the right organs. The differences in these properties between carboxylic acids and their esters can be particularly dramatic.There are other ways to do it. Some compounds are oxidized by liver enzymes to turn into their active forms, for example. But all of these ideas suffer from several complications, which is why I’ve always regarded them as acts of desperation. For one thing, all these metabolic pathways vary a good deal between species. That’s a problem for any drug development effort, of course, but you’ve doubled those headaches (at least) by working with a prodrug. Now you have to wonder, when you finally get to humans, if the conversion of the initial compound will take place to the same extent, as well as about the clearance of the active drug (and, for that matter, the non-productive clearance of the prodrug molecule itself). For a development group, taking on a prodrug can be like taking on two drugs at the same time.There have been all sorts of ingenious ideas along these lines over the years. It’s been my impression that delivery methods of this sort have been more popular among academic medicinal chemistry groups than they have in industry, to be honest. There are all sorts of schemes for targeting active substances to particular organs, or for getting them into hard-to-reach areas like the brain through use of exotic prodrug groups. Most of these don’t survive exposure to the real world, but I can’t turn up my nose at them, either, because these are all things that we would like to be able to do in this business. If weird ideas don’t get tried, we’ll never find out if any of them actually work.And there have been some real successes in the prodrug field, and it’s always an idea that comes up whenever a lead compound series shows some undesirable absorption or excretion. I’ve broached the topic a few times myself on past projects. But every time, we’ve been able to solve the problem by less drastic means – a new formulation, a salt form, or by just plain old going to a different compound in the end. If you can do it by some combination of those, I'd say you're probably better off in the end. (For those who are taking the plunge, you can probably learn about as much as can be learned from the literature here ). Here's an even more recent review.Comments (12) + TrackBacks (0) | Category: Drug Development | Pharmacokinetics November 26, 2008How Slow is Research Today? Here's a Recipe!Posted by DerekThe pace of research has noticeably slowed today here in the US. Most industrial labs will be empty tomorrow, Friday, and through the weekend, and even the academic labs will have fewer grad students and post-docs hanging out in them. I'll be cleaning up some previously run reactions, setting up anything that can comfortably go for a few days, and otherwise getting ready for Monday myself. This is not a day to try any tricky chemistry.I also have a manuscript that I'm working on, and it would be a good use of my time to try to finish up its experimental section. The paper will likely be of interest to the readership here, so I'll be sure to note when it makes it into print. It'll be good to hit the scientific literature again; everything that's gone onto my list for the last year or two has been residual stuff from the Wonder Drug Factory, and there's not much of that left, naturally.And I'll be observing a blog holiday until Monday as well, unless of course, something big happens. (I rather doubt that anything will, and considering what "something big" usually means, I rather hope nothing does). I'd like to wish all the US readers a happy Thanksgiving, and if anyone in the rest of the readership wants to try cooking a turkey, well, it's not as hard as it's cracked up to be. If you soak it in some salt water beforehand, it's quite tasty (my wife and I usually buy a kosher turkey, since they've already been salted). Allow me to finish up by furnishing the details of last night's synthetic work, at home in the kitchen with my two children:Melt 3 tablespoons (43 grams) of butter and two squares of unsweetened baking chocolate (I used a coffee cup set in a pan of boiling water). Beat 3 eggs in a good-sized bowl. Then, in a small saucepan, combine 1 cup (240 mL) of corn syrup and 1/2 cup table sugar (100 g), and bring the mixture to a boil for about two minutes. (It doesn't look at first as if the sugar will go into solution, but it will - you naturally don't want this to cool down, though, once it has). Add the butter/chocolate mixture to the sugar syrup (they're not all that miscible, but do what you can), and add this gemisch slowly to the beaten eggs, stirring vigorously. (As I explained to my kids, if you were to dump these together with no stirring, you'd end up with chocolate-covered scrambled eggs; I try to teach them some technique along the way). Stir in a teaspoon (5 mL) of vanilla extract, 1 1/4 cups of pecan pieces (about 130 grams, I think), and pour the resulting slurry into a pie crust, your own or the store's. Bake about 45 minutes at 375F (190C, gas mark 5 for you subjects of the Queen). Yield: one chocolate pecan pie.Comments (11) + TrackBacks (0) | Category: Blog Housekeeping November 25, 2008Avandia: Trouble, Run Head to HeadPosted by DerekAvandia (rosiglitazone) has been under suspicion for the last couple of years, after data appeared suggesting a higher rate of cardiovascular problems with its use. GlaxoSmithKline has been disputing this association all the way, as well they might, but today there’s yet more information to dispute.A retrospective study in the Archives of Internal Medicine looked at about 14,000 patients on Medicare (older than 65) who were prescribed Avandia between 2000 and 2005. Now, looking backwards at the data is always a tricky business. For example, comparing these patients to another group that didn’t get the drug could be quite misleading – the obvious mistake there is that if someone has been prescribed Avandia, then they’re likely getting it because they’ve got Type II diabetes (or metabolic syndrome at least). Comparing that cohort to a group that isn’t showing such symptoms would be wildly misleading.But this study compared the Avandia patients to 14,000 who were getting its direct competitor, Actos (pioglitazone). Now that’s more like it. The two drugs are indicated for the same patient population, for the same reasons. Their mechanism of action is supposed to be the same, too, as much as anyone can tell with the PPAR-gamma compounds. I wrote about that here – the problem with these drugs is that they affect the transcription of hundreds of genes, making their effects very hard to work out. Rosi and pio overlap quite a bit, but there are definitely (PDF) genes that each of them affect alone, and many others that they affect to different levels. Clinically, though, they are in theory doing the exact same thing.But are they? This study found that the patients who started on Avandia had a fifteen per cent higher deaths-from-all-causes rate than the Actos group. To me, that’s a startlingly high number, and it really calls for an explanation. The Avandia group had a 13 per cent higher rate of heart failure, but no difference in strokes and heart attack, oddly. The authors believe that these latter two causes of death are likely to be undercounted in this population, though – there’s a significant no-cause-reported group in the data.The authors also claim that the two populations were “surprisingly similar”, strengthening their conclusions. I think that that’s likely to be the case, given the similarities between the two drugs. GlaxoSmithKline, for their part, is saying that these numbers don’t match the safety data they’ve collected, and that a randomized clinical trial is the best way to settle such issues.Well, yeah: a randomized clinical trial is the best way to settle a lot of medical questions. But neither GSK (nor Takeda and Lilly, makers of Actos) have seen fit to go head-to-head in one, have they? My guess is that both companies felt that the chances of showing a major clinical difference between the two was small, and that the size, length, and expense of such a trial would likely not justify its results. And if we’re talking about the beneficial mechanisms of action here, that’s probably true. You’d have quite a time showing daylight between the two drugs on things like insulin sensitivity, glycosylated hemoglobin, and other measures of diabetes. Individual patients may well show differences, and that's useful in practice - but that's a hard thing to show in a large averaged set of data. But how about nasty side effects? Maybe there's some room there - but in a murky field like PPAR-gamma, you'd have to have a lot of nerve to run a trial hoping to see something bad in your competitor's compound, while still being sure enough of your own. No, it's disingenuous to talk about how these questions need to be answered by a clinical trial, when you haven't done one, haven't planned one, and have (what seemed to be) good reasons not to. This kind of study is the best rosi-to-pio comparison we're likely to get. And it does not look good for Avandia. GSK is going to have to live with that - and in fact, they already are.Comments (4) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Toxicology November 24, 2008Two Drugs in One? Maybe Not.Posted by DerekSince I was talking about Nitromed on Friday, let me mention another attempt to combine two known drugs into a new therapy. Another Cambridge company whose front doors I walk by once in a while is CombinatoRx. If they'd had that name back in the early 1990s, you'd have assumed that they did combinatorial chemistry, but their plan is to take approved drugs and find greater-than-the-sum-of-their-parts combinations to approve as a single pill.That's not easy. It's hard enough figuring out just how single drugs behave in the real world, and any physician will tell you all about what fun it is to deal with drug interactions. Finding beneficial drug interactions, especially unknown ones, is a real uphill climb. But CombinatoRx thought they had one in the mixture of low-dose prednisolone and dipyridamole.Prednisolone is a well-known corticosteroid which is used to suppress inflammation and the immunen response. Dipyridamole is a multi-mechanism drug that increases the free concentration of adenosine, and it's been used to inhibit clotting and lower pulmonary hypertension. Blood pressure problems are common with prednisolone, and the company believed that the prednisolone dose could be taken down to non-side-effect levels in the presence of the other drug. So they formulated a combination pill (Synavive, CRx-102) to test this out in osteoarthritis patients. The stakes were high - here's a writeup from before the results came out last month.Things did not work out. The Phase IIb study definitively missed its endpoints. Not only did Synavive not compare to prednisolone alone, it didn't reach statistical significance versus the placebo group, either. The stock dropped 72% the next day, and the company has now announced layoffs that total 65% of its workforce.What I have to wonder, though, is how things would have worked out in the long run even if the trial had succeeded. As Nitromed's experience shows, it's a hard business convincing insurers to pay a premium for two generic drugs just because they're now available in one pill. I know that CombinatoRx was making much out of their proprietary formulation, no doubt anticipating such objections. But I wonder if a company in this space would have to actually run a head-to-head against the two-generic-pill dosing regimen to really convince people that it had something to offer. And that would take nerves of steel, for sure. . .Comments (12) + TrackBacks (0) | Category: Business and Markets | Clinical Trials November 21, 2008The Back Door to the Stock MarketPosted by DerekNitromed has been in trouble for several years now. They're a perfect example of a dog that caught a car: a company that was demolished by actually getting its drug on the market. No one wanted to pay for it, though, and after all that expense the company was left worse off than before.Their remnants, though, are still listed on the NASDAQ, and that's more than a lot of more promising companies can say. One of those is Archemix, a company that I see every day on my way to work in Cambridge. They're working on aptamer-based therapies, and are at the stage in their life where (under normal conditions) they'd be thinking about an IPO. Well, they were thinking about that, but. . .these aren't exactly normal conditions, and the company recently announced that it was shelving that plan for now.Enter Nitromed! The two companies have now announced a merger (a 70:30 stock split) which will keep the Archemix name and be listed on the stock exchange like Nitromed. Just add water, and you have an IPO, albeit with some dilution compared to the traditional way. Interestingly, the CEO of Nitromed will be the CEO of the new company, which I gather is coming as a bit of a surprise to the folks in the trenches at Archemix, as you might imagine.But good luck to them all - in this environment, we all need it. Aptamers are an interesting and risky business, but not as risky as developing cardiovascular drugs that no one wants. . .Comments (8) + TrackBacks (0) | Category: Business and Markets November 20, 2008Noisy NumbersPosted by DerekA colleague e-mailed me last night with an observation that he’d heard recently: “Have you noticed,” he said, “that the number we use get less and less precise, the farther away they get from the chemists?”Thinking about it, I’d have to say that’s right, although I don’t think that we can claim any particular credit. After all, we have our feet planted in physics. Our molecular weights are based on the weights of the elementary particles, which are known. . .pretty exactly. And we’ve got a pretty good handle on molecular formulae, too, so we can go around getting mass spectra out to four decimal places and learning all kinds of things from them.But then when these compounds get run through the primary assays, purified enzymes or the like, the numbers start getting fuzzier. Protein preps are all subtly different – ideally, they should be different in ways that make no difference, but then there’s the actual running of the assay to consider. Reproducibility varies, but no on gets worked up about a compound that shows, say, a 3 nanomolar inhibition in one assay and a six nanomolar in another. “Single digit nanomolar” is all we need to know, and it’s good odds that the next one will split the difference and come in at four or five, anyway.But then you go to cellular assays, and things get more complicated. Cells are ridiculously more complex than enzymes, and there are so many more things that can kick around your data. Where did this batch of cells come from? How many times have they divided? What stage of their life cycles are they in, on average? What are they growing on, and in? Are they clean (no nasty mycoplasms?) Even if you’ve got all those things under control, your compounds are going to be exposed to untold numbers of other proteins now, all with potential binding sites and activities of their own. And that’s if they can even get past the cell membrane at all – many don’t, for reasons that are not always clear. No, your cellular numbers are always going to have a pretty good spread in them.But then you go to whole animals, which have all those problems and more. Absorption from the gut and later metabolism are tricky and poorly understood processes, and they’re affected by a bewildering number of variables. Is your compound crystalline? Same way each time? What’s the particle size? How much water does that powder have in it? What are you taking the compound up in to dose it? Have the rats eaten recently? What time of day are they getting the compound? Male rats, or female? Nothing bothering them, no loud noises or change in lighting? Every single one of these things can throw your data around all over the place.But now you’re up to clinical trials, and animal data is as orderly as a brick wall compared to human data. All those variables listed above still obtain, although you've presumably controlled for several of them by the time you're in the clinic. But that's more than made up for by the heterogeneity of your human volunteers and that of your all-too-human clinical staff. (Ask anyone who's worked up close with clinical data, and you'll hear all about it).So we start from chemistry, where if we make a compound once we assume that we can always make it again - not always a warranted assumption, mind you, but mostly true. Then we move to in vitro assays, where you really need to have n-of-3, at least, so you can get error bars on your numbers. And we end up in human trials with hundreds (or thousands) of people taking the resulting drug, desperately hoping all the while that we'll be able to pick out an interpretable signal in all the noise. That's the business, all right.Comments (16) + TrackBacks (0) | Category: Drug Development November 19, 2008Novartis and RealityPosted by DerekI know that it’s not necessarily fair to drag out old press releases, but let’s do it anyway. Many readers will remember a few years back when Novartis was making its big research move into Cambridge, renovating the old Necco candy building and hiring like mad. (We’ll pause for a bit of somber nostalgia at the memory of a large drug company actually hiring hordes of scientists).While that was going on, there was a lot of talk about the way their research site was going to be run. Under its new research head, Mark Fishman, Novartis would "reinvent the way drugs are discovered" (I quote from an August 2003 article from the Boston Globe, behind their subscriber wall now, which irritated me quite a bit at the time). There was a lot of talk about Gleevec, and how this was going to be some sort of model for the future of drug discovery in the organization. (I could never quite follow that one, but I was willing to give them the benefit of the doubt). The whole thing would be a "research operation vastly different from traditional pharmaceutical research", to quote another old Globe article (May 2002).Well, some years on now, the obvious question is: did any of this happen? Novartis as a company is doing fairly well, particularly in comparison to some of its peers. And they haven’t had any massive layoffs, to my knowledge, which puts them ahead of the game these days. So overall, the company has been successful: but is the Cambridge site the sort of place it was supposed to be, according to the original PR?My impression is that it isn’t, at least not to the extent that we were all hearing about back then. I know a number of people who work there, and from the outside, at least, it seems to be pretty much like any other large drug research operation, albeit with less elbow room than usual in some of the labs and offices (a deliberate decision, apparently). I hear the usual talk and the usual complaints. Nothing that goes on over there strikes me as very different from other outfits of that size.And there’s nothing wrong with that. This isn't a slap at Novartis, at Mark Fishman, or at anyone over there - it's a very good research organization. But I do wonder where all that transformational talk went. Is it still a work in progress (which seems to be the official viewpoint)? Did the organization try to change things, and fail? Was there even a clear idea of what this change was to consist of? Was there a decision made at some point that since things seemed to be going reasonably well, that the company should just leave the site to develop as it was? Or was all that talk at the beginning nothing more than, well, talk? I wondered about this at the time, and I suppose I'm still wondering now. . .Comments (21) + TrackBacks (0) | Category: Drug Industry History November 18, 2008Cheese Dip and Hydrochloric AcidPosted by DerekOne of the more wide-ranging on my “Lowe’s Laws of the Lab” list is this: The secret of success in synthetic chemistry is knowing what you can afford not to worry about.That’s because you have to have a cutoff somewhere. There are so many potential things that can affect an experiment, and if you have to sweat every one of them out every time, you’re never going to get anything done. So you need to understand enough to know which parts are crucial and which parts aren’t. I think the beginnings of this law came from my days as a teaching assistant, watching undergraduates carefully weigh out a fivefold excess of reagent. Hmm. Did it matter if they were throwing in 4.75 equivalents or 5.25? Well, no, probably not. So why measure it out drop by drop?Tom Goodwin, the professor responsible for teaching me inmy first organic chemistry course, once advanced his own solution to this problem. Growing weary of the seemingly endless stream of lab students asking him “Dr. Goodwin, I added X by mistake instead of Y. . .will that make a difference?”, he proposed creating “Goodwin’s Book of Tolerances.” I think he envisioned this as a thick volume like one of those old unabridged dictionaries, something that would live on its own special stand down the hall. “That way,” he told me, “when some student comes up and says ‘Dr. Goodwin, I added cheese dip instead of HCl – will that make a difference?’, I can walk over, flip to page thousand-and-whatever, and say ‘No. Cheese dip is fine.’”According to him, a solid majority of these questions ended with the ritual phrase “Will that make a difference?” And that’s just what a working chemist needs to know: what will, and what won’t. The challenge comes when you’re not sure what the key features of your system are, which is the case in a lot of medicinal chemistry. Then you have to feel your way along, and be prepared to do some things (and make some compounds) that in retrospect will look ridiculous. (As I’ve said before, though, if you’re not willing to look like a fool, you’re probably never going to discover anything interesting at all).Another challenge is when the parts of the system you thought were secure start to turn on you. We see that all the time in drug discovery projects – that methyl group is just what you need, until you make some change at the other end of the molecule. Suddenly its suboptimal – and you really should run some checks on these things as you go, rather than assuming that all your structure-activity relationships make sense. Most of them don’t, at some point. An extreme example of having a feature that should have been solid turn into a variable would be that business I wrote about the other week, where active substances turned out to be leaching out of plastic labware.But if you spend all your time wondering if your vials are messing up your reactions, you'll freeze up completely. Everything could cause your reaction to go wrong, and your idea to keel over. Realize it, be ready for it - but find a way not to worry about it until you have to. Comments (18) + TrackBacks (0) | Category: Lowe's Laws of the Lab | Who Discovers and Why November 17, 2008Liable For Generics? You Are Now!Posted by DerekThere was a legal ruling last week in California that we’re going to hear a lot more of in this business. Conte v. Wyeth. This case involved metaclopramide, which was sold by Wyeth as Reglan before going off-patent in 1982. The plaintiff had been prescribed the generic version of the drug, was affected by a rare and serious neurological side effect (tardive dyskinesia, familiar to people who’ve worked with CNS drugs) and sued.But as you can see from the name of the case, this wasn’t a suit against her physician, or against the generic manufacturer. It was a suit against Wyeth, the original producer of the drug, and that’s where things have gotten innovative. As Beck and Herrmann put it at the Drug and Device Law Blog: The prescribing doctor denied reading any of the generic manufacturer's warnings but was wishy-washy about whether he might have read the pioneer manufacturer's labeling at some point in the more distant past.Well, since the dawn of product liability, we thought we knew the answer to that question. You can only sue the manufacturer of the product that injured you. Only the manufacturer made a profit from selling the product, and only the manufacturer controls the safety of the product it makes, so only the manufacturer can be liable.Not any more, it seems. The First District Court of Appeals in San Francisco ruled that Wyeth (and other drug companies) are also liable for harm caused by the generic versions of their drugs. At first glance, you might think “Well, sure – it’s the same drug, and if it causes harm, it causes harm, and the people who put it on the market should bear responsibility”. But these are generic drugs we’re talking about here – they’ve already been on the market for years. Their behavior, their benefits, and their risks are pretty well worked out by the time the patents expire, so we’re not talking about something new or unexpected popping up. (And in this case, we're talking about a drug that has been generic for twenty-six years).The prescribing information and labeling has been settled for a long time, too, you’d think. At any rate, that’s worked out between the generic manufacturers and the FDA. How Wyeth can be held liable for the use of a product that it did not manufacture, did not label, and did not sell is a mystery to me.Over at Law and More, a parallel is drawn between this ruling and the history of public nuisance law during the controversy over lead paint; the implication is that this ruling will stand up and be with us for a good long while. But at Cal Biz Lit, the betting is that “this all goes away at the California Supreme Court”. We’ll see, because that’s exactly where it’s headed and maybe beyond that, eventually.And if this holds up? Well, Beck and Herrmann lay it out in their extensive follow-up post on the issue, which I recommend to those with a legal interest: Conte-style liability can only drive up the cost of new drugs – all of them. Generic drugs are cheaper precisely because their manufacturers did not incur the cost of drug development – costs which run into the hundreds of millions of dollars for each successful FDA approval. Because they are cheap, generics typically drive the pioneer manufacturer’s drug off the market (or into a very small market share) within a few years, if not sooner. Generic drugs will stay cheap under Conte. But imposing liability in perpetuity upon pioneer manufacturers for products they no longer sell or get any profit from means that the pioneer manufacturers (being for-profit entities) have to recoup that liability expense somewhere. There’s only one place it can come from. That’s as an add-on to the costs of new drugs that still enjoy patent protection.Exactly right. This decision establishes a fishing license for people to go after the deepest-pocketed defendents. Let’s hope it’s reversed.Comments (31) + TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System | Toxicology November 14, 2008Sticking It to ProteinsPosted by DerekSo, you’re making an enzyme inhibitor drug, some compound that’s going to go into the protein’s active site and gum up the works. You usually want these things to be potent, so you can be sure that you’ve knocked down the enzyme, so you can give people a tiny, convenient pill, and so you don’t have to make heaps of the compound to sell. How potent is potent? And how potent can you get?Well, we’d like nanomolar. For the non-chemists in the crowd, that’s a concentration measure based on the molecular weight of the compound. If the molecular weight of the drug is 400, which is more typical than perhaps it should be, then 400 grams of the stuff is one mole. And 400 grams dissolved in a liter of solvent to make a liter of solution would then give you a one molar (1 M) solution. (The original version of this post didn't make that important distinction, which I'll chalk up to my not being completely awake on the train ride first thing in the morning. The final volume you get on taking large amounts of things up in a given amount of solvent can vary quite a bit, but concentration is based, naturally, on what you end up with. And it’s a pretty flippin’ unusual drug substance than can be dissolved in water to that concentration, let me tell you right up front). So, four grams in a liter would be 0.01 M, or 10 millimolar, and foru hundred milligrams per liter would be a 1 millimolar solution. A one micromolar solution would be 400 micrograms (0.0004 grams) per liter, and a one nanomolar solution would be 400 nanograms (400 billionths of a gram) per liter. And that’s the concentration that we’d like to get to show good enzyme inhibition. Pretty potent, eh?But you can do better – if you want to, which is a real question. Taking it all the way, your drug can go in and attach itself to the active site of its target by a real chemical bond. Some of those bond-forming reactions are reversible, and some of them aren’t. Even the reversible ones are a lot tighter than your usual run of inhibitor.You can often recognize them by their time-dependent inhibition. With a normal drug, it doesn’t take all that long for things to equilibrate. If you leave the compound on for ten, twenty, thirty minutes, it usually doesn’t make a huge difference in the binding constant, because it’s already done what it can do and reached the balance it’s going to reach. But a covalent inhibitor, that’ll appear to get more and more potent the longer it stays in there, since more and more of the binding sites are being wiped out. (One test for reversibility after seeing that behavior is to let the protein equilibrate with fresh blank buffer solution for a while, to see if its activity ever comes back). You can get into hair-splitting arguments if your compound binds so tightly that it might as well be covalent; at some point they're functionally equivalent.There are several drugs that do this kind of thing, but they’re an interesting lot. You have the penicillins and their kin – that’s what that weirdo four-membered lactam ring is doing, spring-loaded for trouble once it gets into the enzyme. The exact same trick is used in Alli (orlistat), the pancreatic lipase inhibitor. And there are some oncology drugs that covalently attach to their targets (and, in some cases, to everything else they hit, too). But you’ll notice that there’s a bias toward compounds that hit bacterial enzymes (instead of circulating human ones), don’t get out of the gut, or are toxic and used as a last resort.Those classes don’t cover all the covalent drugs, but there’s enough of that sort of thing to make people nervous. If your compound has some sort of red-hot functional group on it, like some of those nasty older cancer compounds, you’re surely going to mess up a lot of other proteins that you would rather have left alone. And what happens to the target protein after you’ve stapled your drug to it, anyway? One fear has been that it might present enough of a different appearance to set off an immune response, and you don’t want that, either.But covalent inhibition is actually a part of normal biochemistry. If you had a compound with a not-so-lively group, one that only reacted with the protein when it got right into the right spot – well, that might be selective, and worth a look. The Cravatt lab at Scripps has been looking into what kinds of functional groups react with various proteins, and as we get a better handle on this sort of thing, covalency could make a comeback. Some people maintain that it never left!Comments (22) + TrackBacks (0) | Category: Drug Assays | Toxicology November 13, 2008The Yield Monster - And Its Friend, The Model MonsterPosted by DerekOrganic chemisty can be a real high-wire act. If you’re taking a compound along over a multistep sequence, everything has to work, at least to some extent: a twelve-step route to a compound whose last step can’t be made to work isn’t a route to the compound at all. To get the overall yield you multiply all the individual ones, and a zero will naturally take care of everything that came before it.Even very respectable yields will creep up on you if you have the misfortune to be doing a long enough synthesis. It’s just math – if you have an average 90% yield, which shouldn’t usually be cause for distress, that means that you’re only going to get about 35% of what you theoretically could have after ten steps (0.9 to the tenth). An average 95% yield will run that up to 60% over the same sequence, and there you have one of the biggest reason for the importance of process chemistry groups. Their whole reason to live is to change those numbers, to make sure that they stay that way every time, and without having to do anything crazier than necessary along the way.When you’re involved in something like this and you know you’re going to be approaching a tricky step, the natural temptation is to try it out on something else first. Model systems, though, can be the road to heartbreak. In the end, there are no perfect models, of anything. If you’re lucky, the conditions you’ve worked out by using your more-easily-available model compound will translate to your precious one. But as was explained to me years ago in grad school, the problem is that if you run your model and it works, you go on to the real system. And if you run your model and it doesn’t work, well. . .you might just go on to the real system anyway, because you’re not sure if your model is a fair one or not. So what’s the point?This gets to be a real problem in some labs. While ten steps is medium to long for a commercial drug synthesis, it’s just the warmup for a lot of academic ones. Making natural products by total synthesis can take you on up into the twenty- and thirty-step levels, and some go beyond that, most horribly for everyone concerned. In such cases, you’d much rather have several segments of the big honking molecule built separately and then hooked together, rather than run everything in a row.But what if you spend all that time on the segments, but you can’t put the things together? The most famous example of that I know happened in Nicolaou’s synthesis of Brevetoxin B. The initial disconnection of this terrible molecule into two nearly-as-awful pieces turned out to have been a mistake. Despite repeated attempts, no way could be found to couple the two laboriously prepared pieces to make the whole molecule, and untold man-hours of grad-student and post-doc slave labor had to be ditched for a new approach. If you want to see the approach that worked, here’s a PDF of a talk about it.But if you go linear, you’re taking the same risk, and the math will absolutely eat you alive. A 90% average yield will ensure that you throw away 95% of your material if you keep going for 28 steps. And keeping a 90% average over twenty-eight steps is just not possible with real-world chemistry, either – and yes, I’ve seen those papers where they do, but I don’t believe them. Do you? Make it 25 steps of average 90%, and three 60% losers, and now you’re down between one and two percent of your material left. Which is no way to live.I note that the above summary of the Brevetoxin synthesis counts 123 synthetic steps. It calculates an average yield of 91%. A 2004 synthesis from Japan comes to 90 steps with an average yield of 93%.Comments (17) + TrackBacks (0) | Category: Life in the Drug Labs November 12, 2008Crestor: Would It Save Any Lives?Posted by DerekShould millions more people be taking Crestor? That’s a real balancing act. You have a decrease in heart attacks, but from a fairly small incidence rate. So at a minimum, you’ll need to balance the costs of those coronary events versus the cost of paying for all that Crestor. And statins are not without side effects themselves, so you’ll need to adjust your figures for the incidence of rhabdomyolosis, among other things. (For example, is the increased evidence of high blood sugar in the Crestor treatment group a real effect, or not? If so, you’ll need to add a bit of diabetes cost to the spreadsheet). In any case, the cost of getting all these people screened for C-reactive protein levels in the first place needs to be added in as well.Naturally, as in any of these calculations, you’re going to have to figure how much should be spent to prevent each excess death, once you’ve decided that these deaths can indeed be considered excess. (Unfortunately, the answer cannot always be “as much as it takes”, since there is not enough money in the world to treat everyone for everything, forever). And that brings up another key question: would putting high-CRP patients on Crestor save lives at all?Well, you’d think so, what with lowering the incidence of those coronary events. But mortality figures are tricky. In all the graphs presented in the NEJM paper, the “deaths from all causes” one is the least compelling. That shouldn’t be a real surprise, since cutting something down in the 1% range isn’t going to bend the curve very much on its own. But if you look closer at the data, things are even | |
