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

Derek Lowe The 2002 Model

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

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

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March 30, 2007

Rimonabant, Slowly

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Posted by Derek

Remember back when Sanofi-Aventis submitted Acomplia (rimonabant) to the FDA? Remember when the FDA told them that they needed more data before it would be approved? That's been over a year ago now - time flies - and now they're saying that another hearing with the agency is scheduled for June 13.

There was an excellent summary of the whole situation by Jeanne Whalen in the Wall Street Journal the other day, which subscribers will already have seen. Here's the article for free access in the Arizona Republic for everyone else. This will take you through the whole story, from the hype of 2004 to the. . .well, uncertainly today.

What's worth thinking about are the (in retrospect, rash) statement of Sanofi's people back then about the huge blockbuster potential of the drug, and the (in retrospect, clueless) statements of various analysts back a year ago. "A brief delay" was one phrase that turned up several times, along with predictions of approval by the middle of 2006. . .make the the end of the year. . .OK, first quarter of 2007. . .fine, fine, by the end of '07.

And what's continued to amaze me is the ability of the S-A management to give no details about what's going on with the drug. A year ago, I thought they'd be forced to talk shortly by investor pressure, but I'm clearly a bit clueless myself. . .

Comments (6) + TrackBacks (0) | Category: Diabetes and Obesity

March 29, 2007

I Want A New Nitro

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Posted by Derek

Quite a while ago (sheesh, five years - this is an old blog, as these things go!), I wrote about a "Chemical Wish List". There are a lot of elements and functional groups that nature has not provided us with, and we could really use them. The earlier post was a request for something the size of fluorine that's electron-donating instead of electron-withdrawing, but today I have another one for the list.

I want a nitro group, or something a lot like it, that's metabolically stable. Nitro's an odd duck, as the structure in its brief Wikipedia entry will show. That drawing is a compromise attempt to represent reality (dotted lines in chemical structures are a giveaway for that). You can draw other resonance structures, all of which approach the truth to greater or (mostly) lesser degrees. Basically, the two oxygens have more electon density on them that usual, and the nitrogen has less. Neither oxygen has a full negative charge on it, but they're closer to it than usual.

And that's what makes nitro interesting. It's quite a polar functional group, and compounds that contain it reflect that. Take a look at the simplest organonitro compound, nitromethane. It dissolves freely in water, and boils at nearly the same temperature, 100 degrees C. Boiling point is a fairly good surrogate for polarity, other things being equal, since it's measuring how well the molecules prefer each other's company in the liquid state, as opposed to flying off on their own in the gas phase. For comparison, methanol (CH3OH) boils at about 65 degrees C, and methylamine is wimpy indeed, fizzing away at about minus 6. Now, there are some molecular weight differences in there which can't be totally ignored, but there's no doubt that nitro is one polar group.

We need polar groups in medicinal chemistry. Those, along with the general shape of the molecule, are the biggest parts of binding energies to our in vivo protein targets. Nitro groups uniquely offer a positive charge right next to a forked arrangement of partial negatives, and I'm sure we could do a lot with that - if the darn things didn't get chewed up in living systems. That nitrogen is nearly as oxidized as it can get (well, there's nitrate anion, true), and there are plenty of systems in the body ready to bring it back down.

That's where the trouble starts. If you go all the way down from nitro, you end up with an amine (NH2). But the intermediates along the way - hydroxylamines, nitrosos, all that kind of thing - are rather reactive and nasty. Those are what give nitro groups their bad reputation in medicinal chemistry - too many of them, especially the ones where the nitro is on an aromatic ring, are experimental (or, gulp, real-world) carcinogens because of those metabolites. The same thing happens to aryl amines, too, because other enzyme systems can oxidize them up to the nasty middle steps. I don't think that they make it all the way up to nitro in vivo, but more perverse things than that happen in biochemistry all the time. For those who don't know this stuff and would like to know more, here's a nice presentation on the basics of drug metabolism - navigate down to #88 in the frame to get to the nitro section.

Now, it's not like there are no nitro-containing drugs. Putting the group on a five-membered heterocyclic ring is often a tolerable move, and there are plenty of examples of that working out. But there's always going to be some suspicion attached to the group, and you're never sure that things are going to work out, since human metabolism can differ from your animal models. Most medicinal chemists opt for caution, and don't put nitro groups on any of their aromatic rings to avoid heartbreak later on. (And of course, there are aliphatic nitros, but those have their own problems).

No, what I want is something that's the size, shape, and polarity of a nitro group, but is rock-solid to metabolism. Sort of a trifluoromethyl group with lots of charge on it. We could certainly have a good time with one of those. . .

Comments (12) + TrackBacks (0) | Category: Life in the Drug Labs

March 27, 2007

ACS Meetings

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Posted by Derek

The semi-annual American Chemical Society meeting is underway in Chicago this week. I'm not there, since duty calls here at Stately Pipeline Manor. (At one point a few months ago, I'd been invited to participate in a symposium that was later dropped. Little did I know that no one would still be employed at the Wonder Drug Factory by the time the meeting rolled around)! C&E News has a blog covering the meeting, and Chemistry World is doing the same.

I haven't actually been to an ACS national meeting in quite some time. They're pretty good-sized affairs, with several thousand attendees, although the size can vary significantly depending on where the meeting is held. There are, naturally, only a certain number of cities that can handle conventions of this size easily - we're not going to be seeing one in Bozeman, Montana or Fort Smith, Arkansas any time soon, although some people might prefer either of those to some of the cities where the meetings are actually held.

A glance at the past meeting calendar shows some locations that come up regularly, and others that pop up for reasons unknown. Boston (site of the next one in August), San Diego, Washington, and New Orleans are regular stops in recent years. Chicago, New York, Philadelphia, and Anaheim make multiple appearances, too. The venues are planned out to 2012, and those stalwarts make up most of the list, with San Antonio and Salt Lake City as outliers. Other places I can remember national meetings showing up are Las Vegas, Atlanta, Miami (not for a while, though, I think) and Dallas.

If anyone has particular nominations for best and worst places to attend one, I'd be glad (and other readers might be as well) to hear them. I'd also be interested in cities off the usual circuit where you'd like to see a meeting take place - yeah, I know, Shanghai, Pune, and Bangalore, but try to think of some others. I've heard the most gripes about Anaheim, personally, for lack of interesting sights, general character, etc., but complaints about facilities, food, and accommodations will also be welcomed. We'll get that Fort Smith booking yet.

Comments (42) + TrackBacks (0) | Category: Chemical News

March 26, 2007

Vectibix Lurches A Bit

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Posted by Derek

Amgen served up a nasty surprise on Friday with the results of a trial they're running on their Vectibix (panitumumab) cancer therapy. It's an EGFR inhibitor (same space as Imclone's Erbitux) and this trial was the first to test a "dual biologics" approach to colon cancer. One group got the standard of care (oxaliplatin and irinotecan chemotherapy, plus Genentech's Avastin VEGF inhibitor), and other other got that plus Vectibix.

Unfortunately, in one of those unexpected results that cancer trials are always delivering, the two-protein-therapeutics group actually showed slightly worse survival data than did the standard-of-care group, and that takes care of that. By itself, this result isn't enough to call Vectibix a failure by any means. But its expected rise to overshadow Erbitux has clearly been delayed.

Imclone's stock price reflects this. Does it ever - my modest short position in their stock is now underwater good and proper. Their stock's up 45% so far this year, with a lot of that in just the last two weeks. But these are early days (he said to himself abstractedly, looking out the window with his brokerage statement in his lap). Both drugs are in similar Phase III trials against colorectal cancer (as that first link, to Bioworld Today, details) and eventually we're going to have about as good a head-to-head comparison as you can expect in this area. Whether that'll be enough to decide anything, well. . .

Comments (7) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials

March 25, 2007

Wandering Through the Hydrides

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Posted by Derek

If you want to get a feel for chemistry, one way might be to wander through the periodic table, picking one particular type of compound and seeing how things change as you go from element to element. (That's a good part of how Mendeleev figured the whole thing out, actually). But you'll want to pick carefully. Chlorides, for example, are rabble, as Primo Levi put it memorably. He was right: one chloride is often very much like another, even when the elements involved are very different - it's as if they've been pulled down to a lowest common denominator. I make some exception for the beautiful green of nickel (II) chloride, or the startling metallic purple of the anhydrous chromium (III) salt, but really, if you can't get something neat looking from the nickel or chromium compounds, you're really in a bad way. Most other chlorides are nondescript white powders. Boring!

Pick hydride instead. Hydrides are, if anything, a bit too exciting sometimes, since they tend to be rather reactive. With water, the usual reaction of a metal hydride is to strip off a proton immediately, giving you the hydroxide of the metal and plenty of lively hydrogen gas bubbling off. Sometimes the whole process is joyful enough for the whole mess to burst into flame.

That'll happen to you with the alkali metal hydrides, over on the left-hand side of the table. Organic chemists the world over know sodium hydride the best. It's a fine strong base - kinetically rather slow, but it deprotonates and spares not. By contrast, you hardly ever see much lithium hydride around. Potassium hydride makes an appearance every so often, though, to muttered curses, since it's usually stored as a slurried suspension in mineral oil and is correspondingly painful to weigh and dispense. It's lively stuff, too, and will set things on fire for you with great thoroughness. The higher alkali hydrides are things I've never seen, and I have no desire to, if their ferocity steps up like potassium does versus sodium.

The next row over (the alkaline earths) feature a compound that gets used every so often in the lab, calcium hydride. It's a good drying agent, because of that water reactivity, and solvents are distilled from a spoonful or two of it to make them anhydrous. But has anyone ever seen or handled magnesium hydride? I sure haven't. It's one of the things that the hydrogen-storage people mess around with, apparently, but you just don't come across it in an organic chemistry lab. Ditto for the other alkaline earths: barium hydride? Never seen it or even thought about it. I don't have access to Scifinder for the time being, since I have no desire for a second mortgage on my house just now, but I see from the web that apparently some people are using the stuff. Maybe it has a great future in organic synthesis, but it sure has no past.

This same pattern holds as you go across the elements. You come across some things that are used all the time (boron hydride, better known as borane), and some that are encountered once in a while (aluminum hydride, copper hydride). There are some well-studied chemicals that are just too reactive and nasty for most people, like phosphine or stannane, and some that are too reactive and nasty for any sane person at all, like mercuric hydride. Some of the nasty ones that are used much more outside of organic chemistry. People who do semiconductor work, for example, know all about the arsenic and germanium hydrides, for example, while few organic chemists have ever touched them.

And then there are some that I'm not sure anyone ever messes with at all. They don't seem to be particularly worse than their neighbors; they just sort of seem to be overlooked. Chemists in the audience - ever thought about titanium hydride? Me neither. Chromium hydride? Never once, until this evening (I wonder what color it is?) These are simple compounds, but even among the simple ones you keep finding all these streets that no one ever walks down. . .

Comments (23) + TrackBacks (0) | Category:

March 23, 2007

Naked Synthesis

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Posted by Derek

There's an unusual article in Nature that several folks have e-mailed me about. It's unusual for several reasons. For one thing, it's synthetic organic chemistry, and there's not much of that in Nature at all - it's an interesting choice of journal on the part of the authors, Phil Baran of Scripps and two of his students, Thomas Maimone and Jeremy Richter. The title also gives away the other odd feature (as a title should): "Total Synthesis of Marine Natural Products Without Using Protecting Groups".

I was talking about protecting groups here just a couple of months ago. In synthesizing complex molecules, they're often necessary, because there will often be several similarly reactive groups exposed at the same time, and you need to be able to distinguish them. Or you'll need to do something severe to another end of the molecule-in-progress, which an amine or alcohol somewhere either won't let you do or won't survive if you try.

The trouble, as any synthetic chemist can tell you, is that protecting groups introduce their own complexities. Ideally, you want to be able to put them on and remove them with no loss of material, but that's impossible. Ideally, you'd want each one to be removable under conditions that won't disturb any of the others, or anything else in your molecule, but that can be a tall order too as they start to add up. And ideally, you'd want all of them to be able to stand up to anything else you'd like to do, until it's time for them to leave, but that's not available in the real world, either. Sometimes a big part of the work (mental and physical) that goes into a total synthesis is figuring out how to manage all the protecting groups.

Baran makes the case that this has gone too far. He's made several complex molecules without protecting anything at all. There's a price to be paid, of course - some of the steps along the way have not-so-impressive yields because of the bareback conditions. But the counterargument is that the overall yield of the synthesis is often higher in spite of this, because there are so fewer steps, and the cost and complexity are cut similarly.

Of course, you can't do this by just plowing ahead with the same reactions that a protecting-group-laden synthesis would use. They're on there for a reason, and that method would send you right into the ditch. Baran tries instead to mimic the biochemical synthesis of these molecules as much as possible, since after all, cells don't use protecting group chemistry, either.

This is an idea with a long and honorable history in organic chemistry, starting with Sir Robert Robinson's startling one-pot synthesis of tropinone back in the 1917. That one is usually taken as the father of all biomimetic syntheses, although it's been pointed out (by no less an authority than Arthur Birch) that this is partly a legend. But it's a legend that has performed function of its reality, leading to a whole series of biologically-inspired syntheses. This latest paper is a call to make biomimetic synthesis the centerpiece of the field again.

I'm sympathetic to that view, but it's not going to be easy. Read closely, the paper shows that this kind of work can be very difficult indeed, even when the biogenic pathways to your target molecules have been studied (which isn't always the case). There are a lot of steps here that required careful coaxing to work in reasonable yields, or at all - no one should confuse the lack of protecting groups with a savings in time. And these difficulties also undermine the claim of reduced cost and complexity a bit, since they represent plenty of time and effort - and if they aren't synonymous with cost and complexity, I don't know what is. Academia may obscure this a bit, since we're only talking graduate student labor here, but it's a real issue.

Where I see this making an impact industrially is in process chemistry. Many times companies work out several parallel routes to an important drug substance, looking for the lowest overall cost. That's where attention to no-protecting-group methods could pay off. Process groups already try to avoid these steps anyway, for the same reasons.

But for the most part, drug substances aren't so complex that they need lots of protecting group manipulation. We could always try to get into more complicated structures through these routes, but this leads to a chicken-and-egg problem. The medicinal chemists generally don't have the time to investigate the picky conditions needed to make no-protection chemistry work, so they're not going to have access to the shorter, higher-yielding syntheses needed to do analoging work. (And there's the real problem that these analogs might need complete re-optimization of the trickier steps each time, which would be a real nightmare). The process chemists would have the time and mandate to work out the no-protection stuff, on the other hand, but if med-chem can't deliver a good drug candidate, then they have nothing to optimize.

The Nature link above is subscriber-only, but you can read the supporting information with all its synthetic details here if you like. It's a pretty big PDF file, though, so be warned. I'd be interested to hear what readers, both academic and industrial, think about this one.

Comments (28) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development | General Scientific News

March 22, 2007

FDA Advisory Panels: Pay, No Play

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Posted by Derek

Jim Hu has a good post on some proposed new FDA rules for its advisory panel members. Some sort of changes have been coming for a while now - here's an op-ed that I wrote on the subject back in 2005. I argued that many of the best scientists and clinicians in a given field already work with the industry (which isn't such a bad thing when you think about it), and that restrictive requirements for serving on advisory panels could do more harm than good.

Well, here's the new proposal: the cutoff is $50,000 in the previous 12 months. At that or above, you won't be allowed on the panel. Between $1 (presumably) and $50,000, you can sit on the panel, but won't be allowed to vote. My guess is that that's going to have a pretty big impact if it goes through, and that we're going to see some very different committee rosters.

Or, of course, maybe we're going to see some new forms of relationships between drug companies and their consultants. That's what happens whenever efforts are made to regulate money in the political world, and it wouldn't surprise me a bit here. There are two ways to look at this: if you're suspicious of the FDA's motives (like, say, Rep. Maurice Hinchley of New York, who has a bill mandating these changes and more coming along), then you'll probably see the whole process as a form of organized bribery, wheel-greasing to get defective drugs past the regulatory authorities. Another way to look at it, though, is that outside experts have something that the drug companies need (expertise, and more importantly, expertise from another point of view than the one from inside the company), and that they're willing to pay for it. This may seem odd, but these consultants don't always tell us what we want to hear.

The tough part is when a drug is on the edge of getting approved or not - it has some good points, some bad ones, and the decision could go either way. That's when suspicions are raised that an extra $50,000 here and there is what tipped things over to approval. I don't see that happening, myself (although readers are invited to submit counterexamples). Many approvals can be honestly argued either way, because these medical questions are inherently one big grey area.

The media reaction to this story is rather more toward the former point of view, though. The Washington Post's take on the story is that ". . .the new guidelines implicitly acknowledge what critics have long said -- that it is possible to find enough qualified experts who do not have ties to drug and device manufacturers." And Gardiner Harris in the New York Times gives one sentence to someone at the American Enterprise Institute, while leaving plenty of space for words from Rep. Hinchley and my own representative, Rosa DeLauro, both of whom are good places to go for "corporate poisoners" quotes.

Well, this is the first act of a rather long session of political theatre. There are 60 days of public comment on this proposal, then more wrangling comes along after that. Then there are the bills in the House, which if things go on long enough will get thrown into the next election cycle, and on it goes. It's worth watching, but be ready for a protracted show.

Comments (5) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | The Dark Side | Why Everyone Loves Us

March 20, 2007

AGI-1067: Dead or Alive?

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Posted by Derek

Pfizer's enormous torcetrapib failure last fall wasn't the only time a company has come to grief in the cardiovascular area, and it's not going to be the last one, either. That's been proven this week by a much smaller company, Atherogenics, and their lead drug, AGI-1067 (partnered with AstraZeneca).

The company is targeting expression of the VCAM-1 protein in blood vessels. That's an immunoglobin that seems to be involved in the adhesion of various blood cell types to the vessel walls, and as such is considered a very interesting target for atherosclerosis. AtheroGenics has been working on a series of drug candidates that interfere with the expression of VCAM-1 (through blocking an oxidative pathway in the endothelial cells) and could thus slow the development of arterial plaques (or reduce the size of plaques that had already formed).

Such is the hope, anyway. AGI-1067 behaved well in animal models, and went through numerous Phase I trials in combination with other cardiovascular agents. That link will also take you through the Phase IIa and IIb trials, which showed some real effects in reduction of plaque volume. Those results led to this Phase III trial (with the acronymn ARISE), which expanded the number and variety of patients while looking at real-world endpoints.

That's just how things should work. You see if the drug is tolerated, alone and with the therapies it's going to be given with. Then you check some primary endpoints, to see if the mechanism you're targeting is really being affected. Finally, you see if that's actually going to do a real number of patients any good: I, II, and III. And, unfortunately, III is where the Atherogenics drug ran into trouble.

They missed their primary endpoint, which was a composite score of cardiovascular adverse events - death, heart attack, stroke, angina, etc. Overall, AGI-1067 was no better than placebo when given along with the standard drugs for this patient population. There's no way to call that good news, and no one's even trying. At the same time, though, the company claims to have seen positive effects in some disease states. What subgroups those are, and how positive those effects were, won't be known until next week's meeting of the American College of Cardiology in New Orleans. It's impossible to say if this is just wishful thinking, or a drug worth salvaging.

That's just what the people at AstraZeneca have to decide. The company's pipeline could use some help (not that this distinguishes them very much these days), so they don't want to walk away from something promising. At the same time, they can't afford to throw good development money after bad, either. But the stakes are much, much higher for AtheroGenics, since this physiological pathway is basically the platform for the entire company. There are doubtless some very difficult and unpleasant meetings in progress, not the tiniest bit of fun for anyone involved. My. . .well, heart, goes out to everyone involved. . .

Comments (7) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development

March 19, 2007

Scientists, All Over

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Posted by Derek

Missed a day or two there - my apologies to the readership. I was out of town, up in Boston/Cambridge (and just in time for a fine March snowstorm). Every time I'm up there, I remember the first time I visited Cambridge, some years ago. I was walking along near Kendall Square and I began to notice that the visible number of thoughtful-looking bearded guys wearing oxford-cloth button-down shirts with the sleeves rolled up and khaki trousers (that is, to a first approximation looking exactly like me) had reached a level unknown to my experience.

It was a strange moment. I'm used to feeling a bit removed from my environment, so to suddenly blend in so thoroughly was a bit of a shock. The same feeling has hit me in just a few other places, mostly around large well-respected universities, and there have been a few isolated incidents elsewhere. I still recall talking with some other chemists at a conference once when one of the group made what is still the only casual conversational reference to Kurt Goedel I've ever encountered (well, other than the ones I've made myself, and I don't trot 'em out too often, for a lot of good reasons).

It can even happen at a distance. When my wife and I were watching the coverage of the first Mars Rover landing, broadcast from JPL in Pasadena, the way the people there talked about the project and the looks on their faces as they awaited word of a successful landing made me realize again that I am in fact part of a tribe, and that these people were members of it, too. We're scattered all over the world, but we know each other when we meet.

Comments (14) + TrackBacks (0) | Category: Who Discovers and Why

March 15, 2007

Lousy Reactions: Reader's Choice

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Posted by Derek

Here's a quick synthetic question for the lab jockeys in the audience: is there a name reaction that has never, ever worked well for you? The Skraup synthesis has a bad reputation, for example - I've never had the pleasure, but I've heard many stories of splattering dark crud and 20% yields.

I suppose we should distinguish between reactions that are supposed to work well and don't, and reactions that no one has ever claimed are nice (like the Skraup). There's a whole category of reactions that will give you 40 per cent yields when other methods will give you 90, but will also give you 40 per cent when everything else gives you zero. I can't say anything bad about those; they are what they are.

On the other hand, even more most reliable transformations can turn on you. I once had a primary alcohol that I just could not protect with a TBDMS group, a difficulty that made me feel like a complete hack until a disgusted colleague or two had to try it on the same substrate and I was vindicated. But silyl groups are usually pretty friendly. For now, let's take nominations for Least Reliable/Most Overrated Reaction. I'm curious to see what makes the list. . .

Comments (73) + TrackBacks (0) | Category: Life in the Drug Labs

March 14, 2007

Schering-Plough Goes Shopping

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Posted by Derek

Schering-Plough woke everyone up with a large surprise bid for Organon, the long-suffering pharmaceutical arm of Akzo Nobel. Many people are spinning this as a good deal for everyone involved, and that may be. But then again, people always seem to say that about mergers and buyouts, and they're not always right, are they?

Organon has strengths in endocrinology and CNS, two areas where Schering-Plough has never had much of a presence (despite a number of shots on goal in the latter one). The problem is, even the companies that have had success in CNS have had to take a lot of shots, because it's that kind of field. No one really understands antipsychotic and antidepressant drugs, for example, and thinking that you do has been a recipe for trouble. The biggest prospect in Organon's portfolio is asenapine, an antipsychotic, which Schering-Plough seems to have their eye on. But that's a drug that Pfizer walked away from last year, citing "a commercial analysis of the compound". It was my impression that that commercial analysis took place after Pfizer got a look at some of the clinical data, though, and I see that I'm not alone in thinking that way (nor alone in my worries about betting big money on drugs in this area).

There's also the question of how much Schering-Plough is paying. When Bayer bought up German Schering (no relation!), they paid around eight times earnings (and that was already more than they wanted to spend, thanks to Merck-Darmstadt). Schering-Plough is paying around 14 times earnings for Organon. As pointed out here, Akzo Nobel was hoping to raise 9 billion by spinning Organon off, and estimates were that an outside buyer might be willing to go as high as 10. Schering-Plough offered 14.5, which news seems to have been greeting by incredulous delight over in Holland, as well it might. Words like "phenomenal" have been used.

There's no word yet (that I've seen) on what will happen to various sites and divisions of the two companies after the buyout goes through. You'd have to assume that there will be some real cuts - that's the only way to make that price work out - and I'd guess that it'll be more on the Organon side. Most of the press coverage has been about how Schering-Plough is picking up all these late-stage drugs, with nothing about the earlier research at all. (Of course, my assumptions about where a drug company will make cuts in research has already been shown to be imperfect, so keep that in mind. . .)

Well, Fred Hassan is a dealmaker, no doubt about it. And it's true that you have to take risks to make it in the drug industry. As (disclosure!) someone who still holds a reasonable amount of Schering-Plough stock, I hope this one works out for him. It'll be interesting to watch.

Comments (18) + TrackBacks (0) | Category: Business and Markets | The Central Nervous System

March 12, 2007

No Shortcuts

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Posted by Derek

I wanted to link tonight to the "Milkshake Manifesto" over at OrgPrep Daily. It's a set of rules for med-chem, and looking them over, I agree with them pretty much across the board. There's a general theme in them of getting as close to the real system as you can, which is a theme I've sounded many times.

That applies to things like "Rule of Five" approximations and docking scores - useful, perhaps if you're sorting through a huge pile of compounds that you have to prioritize, not so useful if you've already got animal data.

He also takes a shot at Caco-2 cells and other such approximations to figure out membrane and tissue penetration. I've never yet seen an in vitro assay for permeability that I would trust - it's just too complicated, and it may never yield to a reductionist approach.

I'm a big fan of reductionism, don't get me wrong, but it's not the tool for every job. Living systems are especially tricky to pare down, and you can simplify yourself right out of any useful data if you're not very careful. The closer to the real world, the better off you are. It isn't easy, and it isn't cheap, but nothing good ever came easy or cheap, did it?

Comments (6) + TrackBacks (0) | Category: Drug Assays | Drug Development | In Silico

March 11, 2007

More Help Wanted?

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Posted by Derek

Back in November, I announced the impending closure of the Wonder Drug Factory, and there were plenty of people who responded with news of open positions. My colleagues and I really appreciated it - a number of interviews (and some placements) resulted.

Since then, many of the folks I worked with have found a place to land. That said, there are still a number of us who are looking, and one common factor has been length of experience. Among my med-chem colleagues, the ease of re-employment has been pretty closely correlated with job level. Associates have been largely snapped up. Less-experienced PhDs have had a harder time, but are gradually finding positions. "And then," he said, "there are people like me. . ."

Well, I do have some possible prospects, but some of them aren't going to be resolved for a while yet, so there's nothing concrete yet. I would, in these circumstances, be very glad to hear of positions that I've missed, both for my own use and for my former co-workers. The people that I know are still looking are experienced med-chem project and group leaders, higher-level people in HTS and assay development, and some experienced pharmacology/biology lab heads. They're all worth talking to if your company has a need - just send along an email and we'll take it from there.

There are a number of companies with advertised positions at these levels (Biogen/Idec, Sepracor, AstraZeneca, Wyeth, Novartis, and others). Of course, when these things are listed, everyone knows what kind of slushy tidal wave of applications hits the HR offices. Any readers at such places who believe that they might be able to help out from the inside (making sure that CVs get to the right hands, etc.) are also welcome to write. Big Pharma, Small Pharma, Biotech - everyone's welcome. And thanks (again) to everyone who's written so far. We'll get everybody employed yet.

Comments (19) + TrackBacks (0) | Category: Closing Time

March 8, 2007

How Not to Do It: More Diethyl Ether (Now With Extra Hardware)

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Posted by Derek

Man, have things changed since I was in grad school. We used to pour all kinds of horrible things down the drain - mind you, this was a good twenty years ago. But you can't do that now, can you?

A respected University of Washington pharmacology professor became a felon Wednesday when he acknowledged dumping a flammable substance down a laboratory sink and then trying to conceal his actions.

Daniel Storm, 62, pleaded guilty in federal court to violating the Resource Conservation and Recovery Act by flushing about four liters of the solvent ethyl ether. He faces a maximum five years in prison and a $250,000 fine when sentenced June 18, although prosecutors have recommended probation under the terms of a plea agreement.

Well, everywhere I've worked, the safety officers have tried to put the fear of RCRA ("rick-rah") into us, and by gosh, it looks like they may have had a point. Turns out that Prof. Storm's lab had several elderly containers of ether which turned up in a lab inspection, and he decided to get out of paying the $15,000 hazardous waste disposal bill. So he decided to take matters into his own hands.

And how: he went after the metal ether cans with an ax, which means that he was lucky not to blow himself up. (A stray spark from the metal could have done the trick, and who knows how much peroxide was in the stuff, for that matter). Why the Monty Python lumberjack routine? Well, the lids were too tight, and according to Prof. Strong, the ax just happened to be handy. (How many times have the police heard that old excuse, eh?) Yep, you can't pour ether down the sink like we used to, and you can't chop open the stuff with an ax like we. . .well, actually, we never used to do that. No one ever has, most likely.

What really ripped it was when he went on to fake paperwork from a nonexistant waste disposal company to make it look as if the ether had been properly hauled away. No, if you haven't clicked on that link yet, you'll have to take my word that I'm not making this up as I go along. But you get the impression that Professor Strong sure was. Makes you wonder if he had been exposed to too many fumes. A spokeswoman for the school says that she's unware of any similar incidents there, and I'll bet she's telling the truth. No, I've seen some stupid things done with diethyl ether, but this one threatens to retire the trophy.

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March 7, 2007

Fish Nor Fowl?

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Posted by Derek

The grad-school advice topic from the other day got me to thinking about another issue in that line. Everyone knows about how hot all the mixed chemistry-biology stuff is (and has been). Chemical biology, biological chemistry - call it what you like, a lot of people are doing it (and a lot of people are getting funded for it).

That's fine with me. I find a lot of the work very interesting (though not invariably), and some of it looks like it could lead to useful and important things. My worry, though, is: what happens to the grad students who do this stuff? They run the risk of spending too much time on biology to be completely competent chemists, and vice versa. Instead of being seen as well-rounded modern scientists, ready to take on the blurred boundaries of the new research, they might end up unacceptable to their potential colleagues in any given discipline.

I'm sure these fears have come up every time a new field of research opens up. ("Organometallics, you say? So, are you an organic chemist or an inorganic one, hey?") They've taken care of themselves in the past, and they probably will this time, too - eventually. But I'd have to think that there's going to be a lag time, which we're surely still in, during which the people who've done hybrid projects are going to have a hard time proving themselves in the traditional categories.

I should qualify that to the traditional industrial categories. Academia, following the hot topics and following the grant money, is surely more more hospitable to the new breed. But many of the tools of chemical biology are still a bit blue-sky for use in the drug industry (or are seen to be), and even the ones that are already in use tend to be used by people who are more easily classified. Probably the smaller companies are out in front on this, having less invested in the standard organizational charts and often being closer to the academic worldview anyway. Thoughts?

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Quietly Disappearing From the Skies

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Posted by Derek

Failure's an orphan, sure enough. We get to hear about the really big clinical failures in the drug industry, the Vanlevs and the torcetrapibs, because they hit the greasy chute just when they're bounding up on the stage, while all the spotlights are on them. But there are plenty of other projects that just sort of evaporate, with no one wishing to call attention to them.

That's well illustrated in the recent case of GlaxoSmithKline. The company updated its research pipeline in its annual report last week, and analysts noticed that eleven drugs had disappeared from clinical trials since the last listing. No press releases were sent out at the time, no conference calls were made. None of the drugs were, individually, expected to be huge parts of GSK's future by themselves - but losing nearly a dozen compounds from the clinic has to hurt.

Among them were a beta-3 agonist for diabetes (solabegron) and a glycoside-based thrombin inhibitor (odiparcil). I wouldn't have been putting a lot of money down on either of them, myself - not that I have any information about the compounds in particular, just that those mechanisms have been graveyards for drug development. Counting the number of beta-3 agonists or thrombin inhibitor projects that have been reported over the years would be a nasty job, and none of them (so far) have made it to market.

There were also several oncology compounds missing, and that's no huge surprise, either. Cancer drugs have the highest failure rates in the clinic - the last estimate I saw was around 95%, which is the sort of number that makes you want to thoughtfully look out the window for a while.

I almost wish that more were made of these failures. It would be painful for the companies involved, but it would give people a better idea of how painful drug discovery can be. I had a friend who was always worried about flying anywhere, and I kept wanting to pop in every few seconds, all day long, with news of yet another plane that had landed safely in Chicago, Atlanta, LAX or wherever, just to get the point across. In the drug industry, though, we have the reverse situation - almost everything we try to put into the air crashes. There should be some way to get the point across that most of our drug candidates never make it, taking all their development money down with them.

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March 6, 2007

Decisions, Decisions

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Posted by Derek

I've had an e-mail from someone going off to grad school in chemistry. He wants to eventually do drug discovery work, and is wondering which way to go:

I have it narrowed down to two departments. One is a large, well funded and well respected university with a specific research advisor that is actively recruiting me for his lab. He is a leader in his field and my place in the lab would be in the capacity of synthetic chemist (making various inhibitors). Although his lab is in the chemistry dept it is more on the bio-organic side. My other choice is a smaller less well respected school with fewer resources (lots of TAing) but I could do total synthesis. I would like to join the first group but obviously I want to be able to get a job. If I joined the first group, would I be unemployable in pharma? With a post doc heavy in synthesis would I be able to get a job?

My answer to him was that I'd go with the first lab. A larger school with a more well-known advisor is worth more than the chance to do total synthesis for a PhD - and just as he mentioned, he can do a synthesis-heavy postdoc if need be. Connections mean a lot - ask someone who's job hunting! - and a PhD advisor is generally the first major source of them at the start of a career. The work described is definitely not so far afield that it's going to mess up later job-hunting.

I told him, though, to be sure to get a varied chemistry background in whichever group he joins. You don't want to get too specialized - for future med-chem employment, that can be a killer. A seminar full of same reaction (or class of reactions) over and over isn't going to impress anyone later on - you need to show that you can pick up new chemistry and get it to work, and that you've had to deal with the things that didn't.

One of the reasons that we like total synthesis people is because they've had a wide range of experience, as well as practice with overcoming difficulties. Total synthesis is probably the most efficient way of getting a wide background in synthetic problem-solving in the shortest amount of time. Admittedly, it doesn't always seem like the shortest amount of time while you're doing it, but you can't have everything.

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March 4, 2007

Calcium: A Backwater

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Posted by Derek

We've had a hundred years or so of nonstop love directed toward organomagnesium compounds (from Victor Grignard, patron saint of getting the reaction named after you and not your supervisor, right on down). So I've always found it interesting that there weren't more organocalciums out there.

Calcium is probably (from an organic chemist's viewpoint) one of the more underused elements in the first few rows of the periodic table. It's always overshadowed by its neighbors. I've never even seen pure calcium metal, as far as I can remember. OK, people distill some organic solvents from calcium hydride to dry them - at least they do in grad school, 'cause in many industrial labs no one distills solvents at all. And there's calcium sulfate as a drying agent (Drierite, by trade name), but people mostly use that for gas drying (calcium chloride, too, although I haven't seen a good old calcium chloride drying tube in a while). For drying liquids, a higher-volume trade, people reach for sodium or magnesium sulfate instead.

And while that's about as high-profile as calcium gets in many labs, those kinds of uses aren't exactly in the center ring. I recall seeing some old work with calcium metal in liquid ammonia, doing Birch chemistry, but I've never heard of anyone actually doing any of it. As far as real organocalcium compounds, the literature is mighty thin. One problem seems to be that the metal itself (unlike magnesium) doesn't just up and react with organic halides very well. Some Grignards, once they get going, have to be beaten down with frantic bucket runs to the ice machine, but not so with calcium.

Chemist Rueben Rieke has gotten around this problem in his usual fashion, by making insanely reactive calcium metal. His calcium work is about ten years old now, but I haven't seen too much follow-up. (One reason might be that Rieke's conditions can be rather painful to use, which difficulty he wisely exploited by forming his own company to do the stuff for other people). But I see that the latest Angewandte Chemie has an organocalcium article from a group of enterprising Germans, so perhaps this stuff might be working its way into the mainstream.

Once people have a reasonable way to get to these compounds, the hard part can begin: finding out what on earth they're good for. You'd have to think that there are interesting reactions and catalysts which can be prepared from calcium derivatives, since they're bound to have their own character. But where to start? An obscure element needs a champion. Boron had H. C. Brown, and Sharpless brought vanadium into vogue for a few years. A host of people lifted palladium from the back shelves to indispensability. Who speaks for calcium?

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March 1, 2007

How Not to Do It: Tertiary Butyllithium

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Posted by Derek

Over here at scenic Lowe Manor (otherwise known as the House that Pharma Has Paid And Will, With Any Luck, Continue Paying For), the dinner table conversation sometimes runs to things like the proper handling of flaming t-butyllithium. Well, OK, the conversation is a bit one-sided, since I'm the only one in the house who's used the darn stuff. My wife has done a lot of bacteriology and molecular biology, fields that don't find much use for pyrophoric organometallics, and I'll keep my kids a good distance from any bottles of butyllithium, thanks.

But I was speaking to the them the other night about the value of experience. Tertiary butyllithium catches on fire, and there's nothing you can do about it. Your best course is to be aware of that, and to expect it. That way, you won't be shocked when you put your syringe into a bottle of the stuff and withdraw it only to find a merry orange flame burning from the tip of the needle. That's a good sign - it shows that your bottle of butyllithium is still good, as opposed to the cloudy, wimpy, hydrolyzed stuff that you should carefully leave sitting in someone else's hood when they're not around.

This pilot light will do you no harm, and will extinguish itself once you put your syringe needle through the next rubber septum. But if you're not expecting it, the sight can come as a bit of a jolt. The consequences are generally not good. There's almost always a tensing of the hand and arm muscles, which tends to depress the syringe plunger a bit, and whooomph: instant flamethrower. I've heard of several completely needless fires that started this way, invariably at the hands of someone who wasn't psychologically prepared to wield some (temporarily) flaming lab equipment with the needed aplomb.

As I mentioned here before, I've had still more practice with fiery glassware. I can attest that a butyllithium flame from the pure substance has a more noble purple color to it than the common orange of the commercial hexane solutions. That magenta hue is from the emission spectrum of lithium itself, and (at least in my case) it did not have a calming effect.

There are, regrettably, even more stupid things to be done with t-BuLi. I'm not sure if I've told this one here before - it's not in the archives at right, so here goes: a friend of mine in grad school was showing a summer undergrad student (hear the chairs of the experienced chemists draw closer) how to do cannula transfers of air-sensitive materials. (This involves hooking up a hose system with needles and tubing, with dry nitrogen or argon gas bled in at the front end of the system to force the stuff over into another waiting flask). There was a double manifold set up in the hood, as usual, to allow a vacuum pump out to remove air from reaction flasks and let nitrogen in to replace it. Somehow, this summer student got the vacuum and nitrogen setting all hosed around when trying to cannulate a whacking load of t-BuLi, and reported back a few minutes later that (although everything was set up perfectly) no butyllithium was appearing.

Feeling the hair raise up on his arms, my friend came to look things over, and saw that indeed, no t-BuLi was showing up in the receiving flask. But there was nitrogen pressure going in, so surely something had to be going somewhere, right? He looked up. . .and realized with a sinking heart that the vacuum manifold at the top of the hood was inexorably filling with the stuff. Now what? I always think in that kind of situation that it's time for lunch, no matter what the clock says.

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