Every few years, you hear talk of a renaissance in natural products-based drug discovery. Well, this news should postpone the next round of optimism for a bit longer: Merck is cutting their natural products program entirely. They've had a long history in that area, but no more. That C&E News item includes an interesting detail:

"The company disclosed that it would also be closing its 50-year-old natural products drug discovery operation based in Madrid after a Merck executive inadvertently included the plan in a PowerPoint presentation to an audience that included Merck employees."

Smooth move. I'm sure some interesting e-mails were exchanged around Rahway and Madrid after that one. When, when will we get the powerful regulatory oversight of PowerPoint technology that the masses have cried out for these many years?

The main thing I remember about Merck's operation in Madrid was when they made a big splash about ten years ago with a weird looking indole/quinone thing that directly activated the insulin receptor. It made the cover of Science and all sorts of press releases, and my biology colleagues starting pestering me immediately. "Hey, you chemists keep saying that there's no point in running a small-molecule screen against the insulin receptor!"

Well, as it turned out, we were right. I assured my co-workers on the next floor that the Merck compound was one of the least likely drug candidate structures I'd ever seen, and that I'd be intensely surprised if it went anywhere. In fact, I told them, seeing it on the cover of Science actually decreased the likelihood that it was anything useful. If Merck really had a small-molecule insulin mimetic, I reasoned, the program would be a real stealth bomber, for fear of sending all sorts of other companies into the same chemical space too quickly. This one had all the signs of the people involved saying "You know, the only thing this stuff is good for is getting on the cover of Science"

So it proved, eventually. The compounds never went anywhere. It looks like the most recent natural product-derived compound that Merck got onto the market was Cancidas (caspofungin), and that was seven years ago. Mevacor (lovastatin) will stand as the modern high-water mark of Merck's natural product work - presumably from now on.

Update: here's the map that I was imagining, thanks to Andy in the comments section. It's on the Worldmapper site linked to below, but I missed it while putting the post together. Most of my speculations turned out to be reasonable, although Venezuela (for one) looks a bit better than I thought it would, and Iran looks a bit worse. Africa and the Islamic world are, as hypothesized, almost invisible.

I’d like to see a map of the world with country size dependent on the number of scientific publications and patents – perhaps you’d want to use publications per capita, or per educated capita. That's a cartogram, and although there are plenty of interesting ones on the web, I haven't found that one yet. The US would loom large, that’s for sure. Japan might be the most oversized compared to its geography, although Singapore would also be a lot easier to pick out. Western Europe would expand to fill up a lot of space, with Germany, England, and France (among others) taking up proportionally more room inside the region and (perhaps) Spain and Portugal taking up somewhat less. Switzerland would swell dramatically.

South America would be dominated, I think, by Brazil, even more than it is on the map. You’d be able to find Argentina and Chile, but I think some other countries (like Venezuela) would dwindle in comparison. Africa, as it does so often in maps of this kind, would appear to have been terribly shrunk in all directions, with a few countries – Egypt, South Africa – partially resisting the effects. Moving on to Asia, India would appear even larger than it is, unless you went for the per-capita measurement to cut it back down a bit, and China would be a lot more noticeable than it was ten (or especially twenty) years ago.

Another region that would basically disappear would be the Middle East and most of the rest of the Islamic world. Iran would hang in there, smaller but recognizable, and you’d be able to find Pakistan, too. But the Arab countries (with the minor exception of Egypt) would nearly vanish. The figures from the Organization of the Islamic Conference (the multinational group involved) show that from 1995-2005, the Islamic countries contributed 2.5% of all the peer-reviewed scientific papers. That’s all the more interesting when you consider the amount of potential funding that washes around that part of the world.

This disconnect has been noticed by the region’s scientists, as well it might. The OIC has designated a committee of science ministers to help with a multiyear plan for modernizing things, but no one’s sure if any real money will be forthcoming. According to this Nature article (headlined "Broken Promises"), the OIC countries allocate less than 0.5% of their GDP to research and development. Most of the money promised just to fund that science committee never showed up. Lip service is, of course, a feature of politics (and politicians) everywhere, but I don't think I'm out of line if I suggest that it's very close to an art form in that part of the world.

And that's a very short-sighted approach. Many of these countries are sitting on huge amounts of money at the moment, which should be invested against the day that their oil runs out (or against the day that the world decides that it's not as desperate for oil as it once was). That latter day will, presumably, be hastened along by the countries who spend more on research. . .

Several recent papers in Neurology offer some interesting ideas on Alzheimer's disease. The one that's getting some headlines today suggests that long-term use of ibuprofen has a protective effect against the disease. Actually, the authors looked at all sorts of non-steroidal antiinflammatory drugs, but the correlation was strongest for ibuprofen. (That may be just because it's used so much, however, and not some intrinsic property of that specific drug). Interestingly, although some NSAIDs have been shown to inhibit formation of beta-amyloid (the protein fragment implicated for many years in Alzheimer's), no particular effect was seen for that class of drugs versus the other NSAIDs.

There's long been a suspicion that a lot of Alzheimer's pathology is driven by inflammation cascades, and although evidence has been mixed to date, this would seem to be good evidence for that idea. (More on this in another post). This wasn't a prospective study - they didn't enroll people just to test this idea - but a huge number of VA patients were studied retrospectively, and the authors appear to have done as much as possible to control for other variables. Of course, in an observational study like this one, you can't control for the biggest possible confounding factor: what if there's something about patients who end up taking NSAIDs more often that also keeps them from developing Alzheimer's? That certainly can't be ruled out, but I don't think there's room for that in most of the headlines. It's going to be tempting for worried patients to start taking ibuprofen to prevent dementia - and that just might work, still - but we really can't be sure without plenty of prospective trial data.

Of course, not everything is good for preventing Alzheimer's. You can apparently add statins to that list. An examination of aging Catholic clergy (mostly nuns) showed no correlation at all between statin use and the development of the disease. This is one of those long-running studies that ends with death and subsequent brain histopathology, too, so it's pretty hard to argue with. Intellectually demanding work, though, does perhaps show a protective effect. Interestingly, this effect was even stronger in the cohort of patients that scored lower in assessment of overall intelligence, which makes sense in a way. (Cue the arguments about whether general intelligence exists, whether it can be measured, and if so, whether it's being measured in the correct way).

On the ever-profitable herbal front, you see all sorts of claims made for Gingko biloba extract and cognitive function, and there are a lot of contradictory studies (many of which, unfortunately, aren't worth much). This latest one won't help much - in the intent-to-treat analysis, no effect was seen. When they controlled for how well patients stuck to the treatment, then some correlations emerged between taking the extract and slower rates of memory loss. Unfortunately, a correlation (at the same level of significance) emerged with stroke and associated TIAs. My prediction: the ginkgo biloba sellers will trumpet the first set of statistics, assuming they need recourse to any data at all, and ignore the second one completely.

Such is the current state of Alzheimer's. To be honest, none of these studies (or most of the others in the same issue) would have been out of place back when I was working in the field in the early 1990s. The field awaits its breakthrough, and has been waiting for a long time. . .

We order chemicals from all sorts of suppliers – big, reputable outfits like Sigma-Aldrich-Fluka all the way down to places that none of us even have heard of before. In those latter cases, the primary question is always whether or not the reagent will actually show up, and the secondary one is how long it’ll take. There are some of those small suppliers who pad their catalog with things that aren’t exactly available, not yet – but hey, they will be if someone orders them. They’ll just tell you it’s back-ordered, and tell someone in the lab to get cracking.

And when you get your compound in, they arrive in various forms. Glass or plastic bottles are the norm, naturally, with the occasional irritating (but presumably necessary) sealed-glass ampoule. But after some time in the lab, you can tell some of the suppliers from across the room. For example, the Japanese company TCI sends a lot of its compounds in normal-looking glass bottles, but these are first put inside capped plastic containers, like larger translucent versions of the ones that 35mm film probably still comes in. And once you taken them out, their glass bottles have these odd plastic labels on them which come up around the screw cap and are perforated around the cap’s border. On the labels, they also have that same thin, fussy, serif font that the Japanese have been using for Roman-style letters for decades (since the war?) and is only in recent years disappearing from their world.

Maybridge, British vendor of all kinds of odd stuff, often sends its compounds in these weird little squat brown-glass bottles with small black caps on them. They must have the world supply of that particular bottle shape tied up, since I’ve never seen one anywhere else. It most resembles the small bottles that solutions for injection are packaged in. So many of the company’s catalog items are in such bottles (or even smaller ones) that it seems wrong somehow when you come across a huge (huge for Maybridge) hundred-gram bottle with their label on it.

Most of the suppliers have neutral-sounding names like those above. They could be chemical companies, vendors of kitchen cabinets, real estate trusts, who knows: Maybridge, Oakwood, Lancaster (now gone, and their blue labels with them). And some of them are unmistakably in the chemical supply business, but rather blandly named (Pharmacore, for example, or Chembridge). Some names are, perhaps, mistakes: the namers of Asinex, for example, seem to have been unaware that the closest Engish word is “asinine”, which means that they have to hope for people to pronounce that “s” as if it were a “z”. (I should mention that both Asinex and Chembridge indulge in one widely hated practice: putting no useful information on their tiny vials other than a catalog number or bar code – Bionet (Key) is a similar offender).

In this dull company, I’m always glad to see the weirdos. I miss the now-purchased-away British supplier called Avocado – green labels, naturally – and always wondered who named them and why. Tyger Scientific makes me wonder if there’s an English major in somewhere at their founding, fond of William Blake. And there’s one company that came into the industry under the glorious name of, I am not making this up, “Butt Park”, and many are the chemists they’ve made stand puzzled in front of the supply cabinet. (I'd provide a link, but I can't find a direct one, and Googling it can be a real minefield).

I refuse to consider that name a mistake. That's a feature, not a bug, and I wish that there were more competition in the category. I would proudly and purposely send business to, say, Batshit Chemical Supply, Inc., even if they back-ordered me every single time.

One recent drug industry setback I haven't noted around here - well, OK, to be more specific, it's a Merck setback, and boy must they be getting sick of those - is the FDA's "not approvable" letter for the Singulair/Claritin combination pill.

As the folks at the InVivoBlog note, it sure was hard, from one perspective, to see that one coming. After all, Claritin (loratadine) has an exemplary safety record and has been on the market for many years now, and Singulair (montelukast) has been selling in the billions of dollars as a stand-alone drug. No doubt many people have taken, and are taking, the two as separate pills. So you combine them and get a "not approvable": right.

The In Vivo people speculated that this might be a safety problem, since the agency has been mighty jumpy about that area recently, but Merck has now told them that safety and tolerability weren't raised in the FDA letter.

Well, what does that leave? Manufacturing? Hardly possible, given the way that these two drug substances are already being cranked out. That, as far as I can see, leaves good old efficacy. You could always argue that putting the two compounds into one pill improves patient compliance, etc., if the combination itself is useful in the first place. But in this case, I'd guess that the problem is that the combo has turned out to offer no benefit over either drug taken alone. Hard to make a case under those circumstance, it is.

And if you look into the history of a Singulair/Claritin idea, that appears to be just the problem. As the Wall Street Journal's Health Blog notes, the companies had already found no benefit for seasonal allergies, compared to either drug standing alone. Supposedly they were able to come up with some sort of nasal congestion data (what a joy that must be) that showed an edge this time, but yikes - how desperate do you have to be to take things to that point, after you've already seen no benefit in the main endpoints?

So why are Merck (and Schering-Plough) spending money on this kind of last-gasp line extension? Surely there are better places to burn cash. I've never been sympathetic to the argument that money spend on promotion is somehow stolen from R&D, but this sort of thing is another matter. Stupid R&D most definitely steals money from smarter R&D, and here's some of it that's made off with the swag.

Drug Discovery Today has the first part of an article on the history of the molecular modeling field, this one covering about 1960 to 1990. It’s a for-the-record document, since as time goes on it’ll be increasingly hard to unscramble all the early approaches and players. I think this is true for almost any technology; the early years are tangled indeed.

As you would imagine, the work from the 1960s and 1970s has an otherwordly feel to it, considering the hardware that was available. And that brings up another thing common to the early years of new technologies: when you look back on them from their later years, you wonder how these people could possibly have even tried to do these things.

I mean, you read about, say, Richard Cramer establishing the computer-aided drug design program at Smith, Kline and French in nineteen-flipping-seventy-one, and on one level you feel like congratulating his group for their farsightedness. But mainly you just feeling like saying “Oh, you poor people. I am so sorry.” Because from today's perspective, there is just no way that anyone could have done any meaningful molecular modeling for drug design in 1971. I mean, we have enough trouble doing it for a lot of projects in 2008.

Think about it: big ol’ IBM mainframe, with those tape drives that for many years were visual shorthand for Computer System but now look closer to steam engines and water wheels. Punch cards: riffling stacks of them, and whole mechanical devices with arrays of rods to make and troubleshoot stiff pieces of paper with holes in them. And the software – written in what, FORTRAN? If they were lucky. And written in a time when people were just starting to say, well, yes, I suppose that you could, in fact, represent attractive and repulsive molecular forces in terms that could be used by a computer program. . .hmm, let’s see about hydrogen bonds, then. . .

It gives a person the shudders. But that must be inevitable – you get the same feeling when you see an early TV set and wonder how anyone could have derived entertainment from a fuzzy four-inch-wide grey screen. Or see the earliest automobiles, which look to have been quite a bit more trouble than a horse. How do people persevere?

Well, for one thing, by knowing that they’re the first. Even if technology isn’t what you might dream of it being some day, you’re still the one out on the cutting edge, with what could be the best in the world as it is. They also do it by not being able to know just what the limits to their capabilities are, not having the benefit of decades of hindsight. The molecular modelers of the early 1970s did not, I’m sure, see themselves as tentatively exploring something that would probably be of no use for years to come. They must have thought that there was something good just waiting right there to be done with the technology they had (which was, as just mentioned, the best ever seen). They may well have been wrong about that, but who was to know until it was tried?

And all of this – the realizations that there’s something new in the world, that there are new things that can be done with it, and (later) that there’s more to it (both its possibilities and difficulties) than was first apparent – all of this comes on gradually. If it were to hit you all at once, you’d be paralyzed with indecision. But the gap in the trees turns into a trail, and then into a dirt path before you feel the gravel under your feet, speeding up before you realize that you’re driving down a huge highway that branches off to destinations you didn’t even know existed.

People are seeing their way through to some of those narrow footpaths right now, no doubt. With any luck, in another thirty years people will look back and pity them for what they didn’t and couldn’t know. But the people doing it today don’t feel worthy of pity at all – some of them probably feel as if they’re the luckiest people alive. . .

This post will have one of those stories that I can’t vouch for personally, and I’m very glad of that. It involves making diazomethane, which will have already gotten the attention of the chemists in the crowd.

Diazomethane’s a very useful reagent, but it has to be treated the right way. You can’t buy it – no one will ship the stuff – so you have to make it fresh. (There are several such reagents). For many years there have been chemicals in the catalogs whose only real use has been to generate diazomethane when needed. Generally this involves treating some nasty N-nitroso compound with base in ether, then distilling over the ether solution of the reagent, which is a distinctive bright yellow.

There’s where some of the trickiness comes in. That diazo group is looking for an excuse to revert back to nitrogen gas, which process comes with an inevitable no-substitutions side order of kaboom. The chemist’s job is to not give it that excuse. That means that you can’t heat the stuff up, you don’t make it very concentrated, and you don’t even expose it to sharp or rough surfaces, because that can be enough right there. They sell distillation glassware specifically for diazomethane preps, with weirdly glossy ground-glass joints.

You can keep your yellow solution stockpile in the freezer for a while, and the temptation is always to make a lot of it so you never have to do it again. That leads to phenomena like the big flask of the stuff left behind when someone leaves the grad school group. One of those surprises (“Is this yellow stuff what it looks like it is? How long has it been in here? And who the hell made it, anyway?”) was the cause of a new lab inspection requirement while I was getting my degree. You couldn’t leave until someone determined that you weren’t passing on any explosive bequests.

Of course, sometimes you honestly need a lot of these things. One of the guys in my group was in that situation early in his total synthesis. One summer afternoon, the power went out in the labs during a thunderstorm, and the head of our safety committee came rolling a big cooler of dry ice down the hall. “Anybody need to store something in the cold?” was the call. “Well,” I said, “we’ve got a couple of liters of diazomethane solution.” “That’s not very funny,” he said. “That’s because it’s not a joke”, I replied, and we moved to the front of the line.

So, what’s the stupidest way to handle the stuff? That’s the story told to me by a colleague. He attests that when he was in grad school, he looked across the hall to see someone involved in making a goodly amount of diazomethane – in a large standard ground-glass-joint apparatus. Oh, dear. How the guy was going to get his collection flask off without running the risk of grenading everything, that was the question. As my friend watched in disbelief, the guy reached up to just twist the darn thing right off. . .and it was stuck. A frozen joint – just the perfect time for it. (This is the point where the audience for this story began to bury their heads in their hands).

My colleague swears that he then watched this maniac pick up a propane torch to sweat the joint loose. I believe that someone may have stopped him in time, but I think the teller of this tale decided to adjourn for lunch at some distant location right around then, so I can’t vouch for the outcome. But if anyone has a more drooling, slack-jawed approach to an ether solution of diazomethane than running a propane torch over it, I’d like to know what it is. Short of maybe using it as an HPLC solvent, I’m out of ideas.

So why is Merck's stock dropping - again?
The FDA just unexpectedly handed them a "not approvable" letter for their latest drug, Cordaptive. Actually, we should stop calling it that, since they also told the company that they're not going to approve that name, either. What Merck's going to do with all their promotional freebies now, I can't imagine.

What's Cordaptive, or whatever it's called, anyway?
That's Merck's newest cardiovascular drug - although the active ingredient isn't new. It's niacin, also known as vitamin B3. It's been known for many years that niacin can both lower LDL cholesterol and raise HDL, as well as lowering triglycerides - in fact, it's probably one of the only things that can do all of those significantly at the same time.

So this is a rip-off, then? Merck's trying to sell vitamin B for $20 a pill?
No, it actually isn't, at least not to the extent you're thinking. The problem with niacin as a cholesterol therapy is that you have to take whopping amounts of it to see an effect. And there's a side effect - flushing of the face, which is basically uncontrollable blushing that can last for hours in some cases. That may not sound like much, but the great majority of people who take niacin at these levels have a problem with it, and a lot of people discontinue the therapy rather than put up with it. If the drug is taken for a few weeks, the flushing reportedly eases off some, but not everyone makes it to that point. By all reports, it's very irritating - and since patients can't feel their cholesterol being high, but can feel their faces burning and turning red, they solve the problem by not taking the niacin.

So why doesn't Cordaptive do the same thing?
A lot of people have tried to find a way to keep the lipid effects of niacin and get rid of the flushing. Merck added a prostaglandin receptor antagonist, laropiprant, to try to block the pathway that leads to the vascular effects. And it seems to help quite a bit, which made the combination a potential winner. Abbott already has Niaspan, a slow-release version of niacin, which also has reduced flushing problems and does about $600 million of sales a year. Niacin therapy itself seems to be pretty safe, although you do want to make sure that liver and kidney function are normal before you start, so the only big question has been what blocking that DP1 receptor might do on the side: can you take that pathway out without causing more trouble?

Well, can you?
Apparently not. Actually, that should be "apparently there isn't enough evidence to say yet" - that's probably more in the spirit of the FDA's letter. They want to see more information about the drug. Problem is, the FDA treats this (properly) as a matter between the agency and the drug company, so they aren't saying what the problem is. And Merck, for its part, isn't saying, either. Investors feel rather left out in these situations - perhaps the most striking one in recent years was Sanofi-Aventis's absolute wall of silence for months about why the FDA wasn't approving their potential blockbuster Acomplia (rimonabant).

Why's this so unexpected, if there wasn't enough evidence given to the FDA?
Well, there seems to have been enough evidence in the same pile of data for the European Union, whose regulators approved recommended the drug for approval a few days ago. Merck must have felt reasonably confident that they'd get the same treatment here. No such luck. And as just mentioned, we don't know if the problem is not enough evidence of efficacy, not enough evidence of safety, or a bit of each.

Why don't you people just make cholesterol-lowering drugs that work better, then, so there's no doubt about efficacy?
Would that we could. Statins basically only lower LDL - they don't raise your HDL. And if you push the statins too hard, patients start coming down with rhabdomyolysis, and you don't want that - ask Bayer. Raising HDL has proven to be a real challenge, too. There are a lot of ideas about how to do it, but the most obvious ones aren't working out too well - ask Pfizer.

OK, then, why don't you just make safer versions of what you already have?
Would that we could. But in almost every case, we have no idea of how to do that. For the most part, either the safety concerns are tied up with the beneficial mechanism of the drug, or they're occurring through side pathways that we don't understand well and don't know how to avoid. And some of those are things that you don't even get a read on until your drug gets out into the market, which is no way to do things, either.

So, why is the drug business considered such a safe bet?
Now, that one I don't have an answer for. Unless it's the conviction that people are always going to get sick, which I guess is a pretty safe bet. And that's coupled with a conviction, apparently, that we're always going to be able to do something profitable about that. And some days, I have to wonder. . .

Dr. Warfield Teague is retiring this year, which makes me feel old. He was one of the professors who helped make me what I am today – in his case, partly by keeping me out of his chosen field of inorganic chemistry. It was a good move on his part; I’d surely have blown something up good and thoroughly when I got to grad school, such are the opportunities in that area.

Unfortunately for both him and for me, his Advanced Inorganic course ended up scheduled for 7:40 AM back in early 1983. I started out my college career with a barrage of classes at that hour, and made every one of them. My sophomore year, I only skipped one class, and I waited for the lightning bolt to descend even for that one. But my junior year I had a professor or two whose lectures could be safely (even profitably) missed, and I began to get in the habit.

Teague wasn’t in that category, though. His lectures were fine; it’s just that they took place so early in the morning. My roommate David and I, both chemistry majors, found it harder and harder to summon the activation energy needed to make it out of the thermodynamic sinks of our beds. Dr. Teague’s threat to come over and teach the class in our dorm room didn’t quite do the trick (while lying there in bed, actually, the idea had a certain appeal). But his threat to start giving top-of-the-morning quizzes did. I showed up, and kept showing up. First year of grad school, now that’s where I started slacking off in my classes in earnest. But not all of the professors I had that year could communicate the facts of their specialty as well as Dr. Teague could for his.

The lab part of the course, that I would have shown up at 6 AM for. I don’t know how he’s done it in recent years, but 25 years ago (not possible, that), we could do pretty much any lab procedure that Dr. Teague would sign off on. There was a requirement that we do at least one low-temperature one, one high-temperature one, one metal complex, and so on. So the dozen or so of us in the class would root around through Inorganic Syntheses or the like, looking for interesting stuff. And there’s plenty of it in there, let me tell you.

In my case, the most memorable included the preparation of fluorosulfonic acid from scratch. Scratch means you start from concentrated hydrofluoric acid, a fine substance for the spirited undergraduate chemist to become familiar with. I can still hear the peculiar whine that solid KOH pellets make when you toss them into a plastic dish of the acid – they’ve a pretty short half-life in there, I can tell you. And I also made the magnesium analog of ferrocene – magnecene, I guess you’d call it – by one of those don’t-be-afraid-of-the-obvious routes: heat some magnesium turnings to about 600 C in a tube furnace, and pass fresh cyclopentadiene monomer vapors over them. Works great. And while you shouldn’t be afraid of the paper synthesis, red-hot magnesium metal is something else again.

While I was thus engaged, my classmates were setting off thermite reactions, making phosgene from carbon tetrachloride (chromium trioxide, five hundred degrees, nothing to it), and preparing titanium tetrachloride from the ground up. (I can’t recommend that particular prep – the liquid “tickle-four” comes out bright green from being around 1 molar in dissolved chlorine gas, so you’re going to want to redistill it, most likely). We learned a fair amount of inorganic chemistry, and more than a fair amount of lab technique. As evidence for that, we all survived.

Whether the latest generation of undergrads will get these kinds of experiences, I don't know. But I'm glad I did, and I'd like to thank Warfield Teague for providing them.

I don’t want to say that this is a trend, but I notice that GSK is saying that they’re going to leave Sirtris more or less alone as well (as Takeda has said they’ll do with Millennium). The researchers in both shops should feel good about that, and not only because they’ll be keeping their jobs. They’re getting a vote of confidence in the most meaningful way that a large company can give that to its employees: by paying you money and not messing with you.

Of course, these deals have two sides to them. I don’t know what it’s like in Takeda back in Japan – my contacts inside the Japanese pharmaceutical industry aren’t extensive. But I think that some of the people at GSK (where I do know a lot of people) are wondering just what motivated their company to spend $720 million on Sirtris rather than on them.

It’s a fair question, even though I don’t have a problem myself with the Sirtris deal (as I said yesterday). But the sirtuins themselves are targets that anyone can work on, and you’d assume that a big outfit like GlaxoSmithKline could, if they wanted to, make a big push into the area and find some interesting things. So why didn’t they? The most obvious reason would be Sirtris had already done a good deal of that work, and it was more economical for GSK to buy it than to redo it. Another possibility is that the chemical space for drug-like hits in that area may not be very spacious, and that Sirtris may have already carved out a good piece of that real estate.

There’s also a bit of Glaxo history to deal with. The company had already, about fifteen years ago, decided to make a great big push into a promising new research area: nuclear receptors. They set up a whole research institute and did a huge amount of good science trying to figure out how these things worked, what they were good for, and how to get drugs that affected them. I got interested in the field in the late 1990s, and it became clear to me very quickly that Glaxo’s effort was the most serious of the bunch (and that included some really substantial research going on at Merck, Lilly and some other outfits). The company had teams of people who seemed to do nothing else than study the structures of these things, generate reams of X-ray data, synthesize huge lists of ligand molecules of every kind you could want, and so on. Just run "Glaxo nuclear receptor" through PubMed to see what I mean.

And what did it get them? From what I can see, not much. Avandia (rosiglitazone) is a nuclear receptor ligand (for PPAR-gamma), but its activity had already been discovered, and it was in clinical trials without a known mechanism. Figuring out how it worked was one of the Glaxo team’s early triumphs. But Avandia has turned out to be famously troublesome, and no others have come to market, despite multiple tries in the clinic. The huge amount of time and money the company spent generated a lot of interesting science, but appears (at least to me) to have brought in not one dime of revenue. (No doubt someone from GSK will correct me if I’m wrong).

So you can see how the company might be wary of starting a big internal effort to explore a massive, complex, and risky new field of biology. Politically and psychologically, it’s probably easier for them to structure this in terms of an acquisition.

Well, I’m back from a brief vacation, and catching up with the news. It looks like the big headline is GlaxoSmithKline’s offer for Sirtris: $720 million, which is a hefty premium (84%!) to what the company was trading for previously. Reckless waste of money, or canny deal?

I lean toward the latter, but I’ve long had a place in my heart for sirtuin research and its potential. It’s still a long shot, but it’s one of the most intriguing ones in the history of medicine. Actually, from one perspective, you wonder how long a shot it is: a biochemical pathway that seems to extend healthy life in yeast, roundworms, flies, and mice would seem to have some odds of doing the same thing in man. A lot of drug programs have been started with a lot less backing them up, albeit for rather less earth-shattering indications.

Of course, Sirtris hasn’t officially been targeting life extension drugs, at least not in the near term. A number of these potential life-extending biochemical pathways are tied up with insulin signaling, which makes sirtuin-targeted drugs a natural for diabetic therapy as well. Sirtris has reported encouraging data for just that indication. If a sirtuin-based drug is going to make it to market, that’s a good bet for how it’ll do it. I note, though, that the company has also applied for orphan-drug status for resveratrol itself for a rare muscle disorder. But they don’t own that parent compound, just its use in this case – the diabetes work is being carried on with second- and third-generation analogs that address some of resveratrol’s problems. (It’s not a particularly stable compound, for one thing).

Once one of these drugs is approved, it’ll have the biggest, strangest potential for off-label use that anyone has ever seen. Oh, that’s going to be something to watch. GSK is well aware of this – I’m not saying that it’s part of their business plan, but when you see their head of drug discovery talking to Forbes and tossing the word “transformational” around, you know that they’ve thought beyond a replacement for Avandia. The Wall Street Journal headlines it like it is: “Glaxo to Buy Sirtris in Bet on Antiaging Reseach”.

That’s the truth, all right, and it’s going to be fascinating to watch things develop. As I was saying here the other day, a drug for aging is a perfect example of something the FDA has absolutely no idea of how to approach. Well, it’s not just the FDA, come to think of it: how on earth would you design a Phase II trial for life extension? How long would it take? What’s your clinical endpoint? And further on, how long will you want to monitor your Phase III patients (recall Pfizer’s recent follow-up of Exubera trial participants? How long will it take before you could be sure that some horrible bargain wasn’t struck along the way?

That’s the lurking fear behind all this research, fit to give Leon Kass the shakes. Life extension tends to give some people the same “Things Man Was Not Meant to Know” shivers as (for example) germ-line genetic manipulation. I’m tempted to cue the theramin music in the background, but I can’t really make fun of this attitude, since I understand where the uneasiness is coming from. In all these cases, we’re looking at real alterations of what we think of as human. Personally, I think there’s room for improvement in what we think of as human, but I agree that we should reach for those improvements carefully. And I can see how the very thought could strike some people as coming close to crazy.

But we’re going to find out. That’s the real import of the GSK news: the money is there to find out what’s possible in this field. I’m happy to hear it. But then, I was a bit euphoric back in 2003 when this news started breaking, and I’ve never really lost that feeling. We shall see.

Just wanted to let everyone know that there probably won't be a post for Monday - I'm doing some traveling, and will have irregular access to the internet. No doubt huge stories will break during the day, while I'm unable to comment on them! At any rate, we'll see if I can get something up for Tuesday. See you then!

File this under “does no one any good”. As many of you will have seen, JAMA just published a report on various studies that Merck has conducted and published over the years on Vioxx. The conclusion was that the company basically wrote the papers, and then went shopping for well-known academic names as authors. No, this one isn’t going to be good for anyone involved.

There seems little doubt that this practice does go on. I’ve never been in a position to see it happen, but it’s been reported for years. There are whole companies whose business is “scientific writing and communication”, and some of these seem to be in the business of turning studies into manuscripts, with no mention of their work in the final version. (The JAMA article found evidence of this sort of thing as well).

Scientific authorship is a messy business, true, and there are a lot of journal articles whose entire list of authors might have trouble with a pop quiz on the details of the paper. It is, in my mind, perfectly acceptable for one or two people on the author list to do most of the writing, with everyone else contributing suggestions and revisions. That’s how every paper I’ve been on (or written) has been done. But the worst of these Merck cases look like a search for a lead author or co-author, which is just unacceptable.

At least one of the authors named in the article is disputing its conclusions. Stephen Ferris of NYU says that he was no figurehead, and calls the JAMA paper “egregious” for having done no follow-up with the people it names. I suspect that there will be others in his category – the JAMA offices are getting a lot of testy e-mails this week, I’m sure. Of course, even the guilty are going to be sending them, since no one wants acquiesce to the label of “paid shill for publication”.

And that’s the problem. I can believe that the JAMA authors (Joseph Ross of Mt. Sinai et al.) could have cast their net too widely as they dug through the piles of discovery documents from the Vioxx litigation. But, unfortunately, I can’t believe that all their examples are mistaken. Enough chicanery goes on with authorship in purely academic settings – I can well believe that it happens in industry/academic collaborations.

But that’s the problem right there: the idea behind such a collaboration is, at least partly, to lend credence to the study’s results. Rightly or wrongly, industry studies on marketed drugs are perceived as needing the help. It’s the money involved, of course. When an industrial group publishes a paper on cell physiology or on a new method for cleaning up palladium-catalyzed reactions, no one doubts the results. But when it’s something that might have a direct and immediate effect on millions of dollars in revenue, doubts naturally set in. They always will, even if the research is beyond reproach.

And that’s why this ghostwriting business just makes the problem worse. I haven’t seen anyone suggesting that the Merck studies themselves are bogus – they had damn well better not be – but by playing games with the external author list, the company invites suspicion. I’m willing to bet that many people outside our industry who have just read the headlines on this story have assumed that the results were cooked up, just like the authorship. This is not what the industry needs. It never has been, and we need it less now than ever.

If we’re going to win back the trust of the general public – which we’ve lost, in case anyone hasn’t noticed – we’re going to have to cut out the shortcuts, stop the doubletalk, and act as if what we’re doing (drug discovery) is something to be proud of. Sure, this is a business – we sell improved health for money, and since it sure costs money to do it, there’s nothing in that transaction to be ashamed about. So why are we acting as if the only way to do business is under the cover of darkness?

We’re not going to have much of a business if these practices keep going on. Want price controls, real industrial-strength ones? Want lots and lots of marketing restrictions? Want the FDA to raise the bar for approval to levels never before seen? Want flocks of lawyers beating their wings, circling around our every move? Just keep it up, just keep this stuff up. We’ll get all that and more.

There have been several articles in Nature recently about performance-enhancing drugs. But these aren’t steroids or blood-cell therapies: they’re performance enhancers for scientists and engineers. Chief among them are Ritalin (methylphenidate), Provigil (modafinil), and various beta-blockers, to enhance concentration and wakefulness. The whole topic came to the fore last December, in an article suggestively titled "Professor's Little Helper". Here are the results of their informal readership poll. It's not a huge trend, at least not yet. The fraction of their self-selected sample who had never taken any such compound was in the solid 70% range, and you'd expect people with some experience to be disproportionately represented in such a poll. But usage is out there, nonetheless.

The first question to ask in these situations is, do such drugs work? As you’d guess, there’s no controlled data set to work with. There is, under current regulations, absolutely no way that any company with such a compound would run a trial for cognition enhancement in otherwise healthy people. The FDA has made it clear over the years that they are in the business of regulating drugs that help sick people, not ones for people who have no disease at all. In fact, I don’t think that the current regulatory framework even accommodates the idea of making people “better than well”, and if someone proposed such a study, it’s a solid bet that the FDA would turn it down.

So, in the absence of anything rigorous, we have a flood of anecdotal data, which is what the Nature pieces are full of. Take that along with the many reports of students using these drugs, and you have something significant going on, which has been coming on for a while now. Back when I used to work on Alzheimer’s, we used to speculate about what would happen if we ever did come across something that usefully enhanced human memory. I was sure that a large off-label market would develop among college students. I have to admit, I never considered their professors.

But do they work? Well, I’m willing to stipulate that they do, but I’m not sure to what extent. One confounding variable, which will be very hard to address outside of a controlled trial, is the placebo effect. I have to think that there’s a strong one in this area, that if you think you’ve taken something that helps your concentration and memory, that those functions will measurably improve. How much this counts for is impossible to say – but again, I’m willing to stipulate that there are pharmacological effects above and beyond placebo. In other words, I believe that a controlled trial of healthy individuals would, in fact, show improvement in cognition while taking such compounds. How much, and in what particular tasks, and for how long, and across what subgroups of people, and across what particular dosing regimens, and in what proportion to objectionable side effects, I have no idea. But I think that there’s something there.

And there will be more. I feel sure that other compounds will be developed that affect normal cognition in what are (at least under some circumstances) are beneficial ways. They will not, however, be approved for that purpose. That’s a long, long way off. They’ll be approved for Alzheimer’s, or sleep disorders, or some category of attention deficit disorder, which is how we have the compounds we have now.

This situation is similar to various possible anti-aging therapies. There, too, I think that compounds will come eventually that should be able to show benefits, according to what we understand about aging in other species. But they won’t be approved for that. They’ll be approved for diabetes, most likely, considering the strong links between insulin action and lifespan, or possibly for other slow-developing degenerative disorders. But if aging itself is a slowly developing degenerative disorder, what then?

I’ve been meaning to write something about this story for a while, but one of the problems has been that I’m still quite divided about what I think about it. (Normally my opinions come to me more quickly, for better or worse). Some background: people who’ve known me personally for a while generally know that I’m personally very much opposed to chemically altering the way that I think or feel. I never drank in high school, for example, which I can tell you made me stick out a bit in late-1970s Arkansas. Nor did I in college or afterwards; I still don’t drink now. And that personal prohibition goes even more for other recreational drugs, as you’d imagine.

My reason for that has long been that I enjoy my brain the way it is, and have seen no reason to mess up its function for fun. But the advent of cognition enhancing drugs is a scalpel to dissect that line of thought. What if the ingested chemicals add to some of the parts of my brain that I value the most? That “mess up its function” clause has been taken out and flipped upside down. And what if it’s for work, and not for recreation? Is that more allowable, because it’s somehow less frivolous? (All right then, what if I were to enjoy having a better memory, which I likely would?) That gets to a less creditable reason for my objection to alcohol and other such drugs – perhaps I’m not just objecting to them on practical grounds. Perhaps I’m objecting because I don’t want other people to have a good time, at least not like that.

Food for, well, thought. I’m still working this one out, I have to say. The issue of caffeine will come up as I do – I don’t drink tea or coffee, actually, having never wanted to end up in the position of having to drink either to function. But I don’t object to caffeinated soft drinks, although I don’t generally seek them out. But I have, when I’ve needed to stay awake – so how high a horse can I get on, anyway? Caffeine is a good proving ground for positions on the newer compounds.

Comments are, as always, welcome. I suspect that this is one of those issues that everyone has an opinion on. . .

A recent interview in Nature Reviews Drug Discovery with John Powers, formerly of the FDA, points out some problems in designing antibacterial drug trials. Some of these are unique to this area, although others we're stuck with wherever we go.

For one thing, it’s surprisingly hard to make sure, when you’re selecting patients, that the people you’re letting into the trial have the disease that you’re trying to treat. The example used is that some 5% of the patients who present with cough actually have pneumonia. Pneumonia is a very good disease to treat with antibacterial drugs, but you’d better make sure that your patients actually have it. There are some tests available to make sure that a given pathogen is present, although they aren’t available in every case you’d want them to be. If you don’t have such a screen, you risk having a very heterogeneous patient population, which will likely as not obscure the effectiveness of the drug you’re testing.

Then there’s the related difficulty in treating some conditions that you’d think would be clear cases for antibacterials: ear infections, for example. The problem is, it’s surprisingly hard to show benefit for some of these things with existing drugs. The underlying infection may be hard to get to (poor circulation in the infected area), or it may be an intrinsically heterogeneous condition like sinusitis. (That can be the result of umpteen different sorts of bacteria, or it could well be something viral, or several varieties of fungal infection, or allergies, what have you). There’s no point in running a head-to-head with an existing medication in these cases; you should run against placebo. That'll be enough of a challenge.

Another problem is that some of the bacterial diseases progress rather quickly – ahead, in some cases, of our ability to usefully diagnose them. That presents a real challenge for a clinical design, one that is dealt with, in many cases, by not attempting to gather rigorous clinical data under these conditions at all. In this field, diagnostic tools have to be fast if they’re going to be of much use.

There are two sides to all these problems: not only do you want to get the drug to the people who need it (and who will respond to it) the most, you want avoid giving it to people who won’t respond at all. That’s not just for the reasons given above (it’ll mess up your data), although that’s enough all by itself. No, the other problem is that spreading your drug around to inappropriate patient populations will just bring on resistance even faster. That’s going to happen no matter what, of course – the key is to have it happen as slowly as possible.

Not many chemists come into the drug industry knowing very much about biology. I certainly didn’t, not on the level that was needed. It’s not surprising, but it’s also not as much of a handicap as you’d think, at least not at first.

That’s because the first job of a new hire in the med-chem department is to crank out compounds, and that goes for both the PhD and Master’s levels. (Those roles diverge as time goes on, though). But with a few obvious rules in hand (no hot reactive functional groups, no huge greasy monster molecules, etc.), a person can contribute reasonable-looking compounds pretty quickly. No biological knowledge needed.

But if you’re going to be more valuable than a new hire (and as time goes on, you’d better be), then you have to start picking up some more of the broader science of drug discovery. That turns out to involve a lot more than chemistry, which is one of the things that chemists have to get adjusted to. If you’re going to move up to the point of being considered to lead a new project, you’re going to have to show that you can converse with the folks who know protein expression, assay development, molecular biology, PK, toxicology, and so on. You’re not going to be expected to come in and solve their problems (although if you do manage to solve one once in a while, it’ll do both you and them some good). But you are expected to understand what they’re talking about.

So that’s a piece of advice I can give to new chemistry hires in this business: get ready to learn everyone else’s business, too. Listen up when the people from the other departments talk about what they’re up to, and especially when they complain about their problems. Try to understand why they’re complaining, and ask them (especially one on one) about what they usually try when this sort of thing happens. The occasional paranoid might think at first that you’re compiling info in order to mess with them later, but you shouldn’t be the sort of person around whom that suspicion credibly lingers. In general, if the people in those other groups are any good at all, they’ll be glad to tell you what’s going on, and you’ll pick up a lot of practical knowledge.

The consequences of not doing this sort of thing become more severe as time goes on. At one of my former companies, we once brought in a job candidate from BNP (Big Name Pharmaceuticals). He’d been around seven or eight years, enough time to be considered fairly experienced. But people at that level vary a lot, and he was (as it turned out) on the low end. When we’d ask him about, for example, any formulation problems he’d had to deal with on his project compounds, he told us that well, he didn’t usually go to those meetings, his boss did. And when we asked him about how he got along with the PK group – well, they were over in another building, and he hardly ever saw them. And so on, and so on.

He was well along to being crippled by the way things were done at BNP. Actually, it may have been more the way he was doing things. From talking with other people from that shop over the years, it’s clear that it didn’t have to be that way – if you made the effort, you could go to those meetings, and if you took the time, you could go over to those other buildings and show your face. But you didn’t have to, and this guy (since he didn’t have to) didn’t bother to. And by keeping to his burrow, he hadn’t learned nearly as much as he could have. We didn’t make him an offer. So talk to people, talk to people outside your field. If you’re any good at all, they’ll learn something from you, too.

If today's post didn't waste enough of your time, here's another way to carve something out of the economy: name all the elements, in any order but correctly spelled, in fifteen minutes.

I scored a 97 - forgot some of the more recently-named transition metals, and I didn't even bother with the placeholder names for 112 and up. Enjoy - and if you score higher than I did, don't forget to note that fact in the comments. Not that I have to tell anyone. . .

Hexane (or its cheaper, less well-defined cousin, petroleum ether) is the proto-solvent. Light and thin, it’s the weakest at actually dissolving anything, so it’s the background to most stronger mixtures in a purification. Like most other solvents, though, it’ll strip the oils right off your skin, leaving you spiderwebbed with white lines across your fingers and in need of some lotion. Its smell isn’t pleasant, but it doesn’t really stink, either. A nonchemist would easily place it in the oil / kerosene / gasoline end of things, which is exactly where it belongs.

When I first encountered ethyl acetate back in college, little did I realize that I was picking up the scent of the rest of my life. I've been in the lab ever since, and so has it. Pleasant, unspecifically fruity, vaguely bubblegum-like, the smell of that solvent is a daily companion to almost every synthetic organic chemist in the world. Mixed with hexane in different proportions according to your needs, it runs the majority of chromatographies in the world. Squirt bottles of it sit around on benches. By now, it’s an old, old friend, and the smell of it says that I’m actually getting something done.

Ether (the real ether, diethyl ether) seems like it’s close to not being there at all. No long for this world, it’s supremely light, and evaporates so quickly, that it just barely holds on to the liquid state. It has a slightly dangerous overtone to it, since it can ignite so easily and forms explosive peroxides if it’s left sitting around. The somewhat smothering smell can’t quite be described, but is instantly recognizable. Its oxygen atom gives it more dissolving power, so ether/hexane mixtures are good for delicate separations, although often impractical on a larger scale. To me, ether is sort of a lighter, stronger hexane, in the relationship that titanium has to steel.

Methanol, on the other hand, has no smell – no smell whatsoever to me, at any rate, despite what that Wikipedia link says, although I think I can tell it from air. Pure lab ethanol smells great, but methanol is a blank to me. It’s the most watery of the common solvents – it’s lighter, but that OH group gives it some surface tension, which (along with its bizarre weight) is one of water’s defining characteristics. You notice the difference, compared to thin, slippery hexane or ether – methanol is a solvent with some body to it. It’s powerful stuff in chromatography, too – one per cent added to a weaker solvent will totally change things.

Do you call it dichloromethane or methylene chloride? The latter probably gets more use, and rolls off the tongue a bit more easily. This stuff is like the demon form of hexane – it has no oxygen atoms like ether or ethyl acetate, but is a pretty strong solvent, in what always seems a mysterious way. With another immediately recognizable but hard to describe smell, its odor is the prototype of “chlorinated”. But the thing that stands out the most is its weight. This is the only common solvent that’s heavier than water, and you can build up your arms doing curls with jugs of the stuff. We don’t use its even denser cousin chloroform all that much; it would be even better bodybuilding material.

Acetone is one of the solvents familiar both in and out of the lab: nail polish remover, without the added scents. You hardly ever run an actual reaction in the stuff, though, and when you do it feels a bit odd. That’s because acetone has become the default flask-rinsing solvent of the chemistry world. I’m not sure when that was settled, but it was decades ago: a perfectly respectable solvent, stuck in the role of janitor to all that brown, red, and yellow stuff stuck to the inside of a million round-bottom flasks.

So Takeda has surprised the folks at Millennium with a buyout offer. (They're battening down the hatches over in Japan, and looking for something new). I know several people over at the latter company, and I can imagine that yesterday was one of the less productive days around the labs. No doubt there was a lot of initial fear that this would be a Pfizer-style deal (see below), but as the day went on that didn’t seem to be the case. I’m told that retention bonuses are being offered, along with several other features to try to keep the Millennium operation running.

Takeda’s been increasing its US presence over the years. Signing up with Abbott to form TAP (Takeda-Abbott Pharmaceuticals) some years ago was one step, as was recently buying out that entire partnership. They bought San Diego-based Syrrx a couple of years ago, and now they have a foot on the ground in Cambridge for oncology research. The Syrrx site is now "Takeda San Diego", but interestingly, Millennium is apparently going to keep its name. I also find it interesting that the company hasn’t decided to put up a big research site in one location and call it “Takeda – US”, but have rather taken the retail approach.

How easy managing those sites will be depends on what approach they take. For now, it looks like they’re going to take the easier one, which is to let Millennium carry on in their own style (albeit with more money). We can debate the wisdom-to-folly ratio of that another day. But overall, it looks like the Japanese see something in the smaller US companies that they don’t have themselves, and would like to try to buy. The lighter their touch, the more likely that what they’re after will actually still be around once the checks clear.

Contrast that to, say, Pfizer’s purchase of Sugen, or Lilly’s purchase of ICOS, or J&J’s purchase of Scios. In those cases, the larger companies were in it to buy a drug (or a few possible drugs), and that was that. Medicinal chemists? Pharmacologists? Those they already had. What they needed were the clinical candidates or marketed compounds. The folks in the small-company labs quickly found themselves getting those “What, are you still here?”. And pretty soon, most of them weren’t, voluntarily or involuntarily.

As mentioned yesterday, I would have to say that Mannkind is in big trouble. I’d never heard of the company until the Wonder Drug Factory was closing back in Connecticut, but Mannkind was moving some of their operations into the state around then and interviewed a number of my former colleagues.

The whole inhaled-insulin idea had already taken some pretty severe blows. The massive failure of Exubera was the biggest, although a creative person could always argue that a better product with a more convenient delivery system could succeed in its place. But then Novo Nordisk and Eli Lilly (serious diabetes players, both of them) got out of the area before they’d even launched, deciding that it was better to write off their whole investment than to try to bring it to market. That didn’t help, which is one reason that Mannkind stock was down in the single digits, despite the company's efforts.

Well, as of yesterday it’s down in the really low single digits. And I honestly can’t see how they’re going to revive their flagship program if the Pfizer lung cancer data are real. The FDA is going to be very, very cautious about allowing any sort of inhaled insulin trials to proceed. I’d think that you’d have to show that your product is different from Exubera in its carcinogenic risk just to get one off the ground, and frankly, I have no idea how you’d do that. Anything that could will take years to develop and validate.

This latest result also shows some of the real difficulties and risks of drug development. After all, Pfizer and Nektar spent a very long time developing Exubera. The product was delayed and delayed while more and more clinical work was done. But in a slow-starting condition like lung cancer, those years may still not enough to quite pick things up by the time a product makes it to market. Think of what might have happened if Exubera had been a success. . .

And that brings us back to the regulatory pre-emption topic of the other day. This illustrates why either extreme of that argument is untenable. On the make-‘em-pay side, you have trial lawyers arguing that if companies just wouldn’t put defective products on the market, well, they wouldn’t have anything to worry about, would they? Test your drugs correctly and things will be fine! But Exubera’s pre-approval life was as long and detailed as could be. The testing went on and on – and after all, insulin itself has been on the market for more than half a century. What more would a company need to say something is safe?

Then there’s the other side – total pre-emption, which says that the FDA is there to regulate and sign off on safety and efficacy, and by gosh we should have them do it. Once this mighty agency gives its stamp of approval, that settles it. But again, the FDA put Exubera through all kinds of paces. If every drug took that long and cost that much to develop, we’d be in even worse shape than we are now, believe me. So what’s the agency to do?

The truth, as far as I can see, is that no one can guarantee the safety of a new drug. If you want to take that further, guaranteeing the safety of an existing drug isn’t possible, either. Every known drug is capable of causing trouble at some dose, and every known drug is capable of causing trouble at its normal dose in some people. Every new drug has the possibility of doing things no one ever anticipated, once it gets into enough patients for enough time. Every single one.

Complete safety doesn’t exist, and never has. You can have more safety, if you’re willing to take enough time and spend enough money. But you can take all the time we have on earth, and spend all the money available, and you still won’t be able to promise that nothing bad will ever happen. Pretending that either the drug companies or the regulatory agencies can make that fact go away is a position for fools and demagogues.

I don't usually do more than one post a day, but this really caught my eye. In an ongoing review of Pfizer's (now discontinued) inhaled insulin (Exubera), an increased chance of lung cancer has turned up among participants in the clinical trials. Six of the over four thousand patients in the trials on Exubera have since developed the disease, versus one of the similarly-sized control group. Six isn't many, but with that large a sample size, it's something that statistically can't be ignored, either.

The concerns would have to be, naturally, that this number could increase, since damage to lung tissue might take a while to show up. This, needless to say, completely ends Nektar's attempts to find another partner for Exubera. Their stock is getting severely treated today (down 25% as I write), but things are even worse for another small company, Mannkind, that's been working on their own inhaled insulin for years now (down 58% at the moment).

There's no guarantee that another inhaled form would cause the same problems, but there's certainly no guarantee that it wouldn't, either. Whether this is an Exubera-specific problem, an insulin-specific one, or something that all attempts at inhaled proteins will have to look out for is just unknown. And unknown, in this case, is bad. It's going to be hard to make the case to find out, if this is the sort of potential problem waiting for your new product. Inhaled therapeutics of all sorts have taken a huge setback today.

Time for another quick quiz on whether you have what it takes to be a big-time medicinal chemist. Prepare for some not-so-welcome old friends to visit you yet again:

1. Your two main assays refuse to act as if they’re part of the same project. Most of your potent compounds in the first enzyme assay don’t do much against the cells, and the best cellular compounds are no great shakes in the enzyme assay. There’s a narrow zone of overlap, but it doesn’t look big or robust enough to base the whole project on. Do you pursue the cellular activity, on the theory that that’s the effect you’re looking for, or pursue the enzyme activity (on the grounds that it’s the right target, and you just have to get the things into the cells), or consider revamping the assays completely, or what?

2. In the next case, your disconnect doesn’t occur until you get to metabolism and PK. When you run your compound across liver enzymes, they grind it into dust. But you did that after you dosed the animals, you buckaroo, and not only did the compound seem to work OK, but its blood levels weren’t bad, either. So how come it looks as if it should be disappearing? The most destructive of the enzymes, by the way, was the human one. Are you worried about that, or not?

3. The project you’re on has a compound profile as a goal – so much potency, at least so much selectivity, and the like. As time goes on, there’s one selectivity assay in particular that you just can’t seem to shake. The only time you see a decent separation between your activity and the one you don’t want is in a compound series that you don’t like – they’re big and greasy, and although they look very active in the enzyme assay, they never perform as well as they should in the animals. But it’s starting to seem as if you have a choice: good properties or selectivity, but not both at the same time. What to do?

4. OK, let’s back up some. You’re working on a project that hasn’t really made it to the medicinal chemistry stage. The screening folks have run the target, and forwarded you their data. Nothing shows up really potent, but there are some 500-nanomolar things scattered around. And “scattered” is the word, all right. You probably have two dozen near-singletons in that range – nothing seems to show much of a robust effect across a given class of compounds. But this is a target that everyone wants to start a program on - it's hot, it's happening. How do you proceed?

Ever hear of tunicates? They’re these little sea squirt creatures that sit around day and night, filtering sea water for food. The weird thing about them is that although they have blood, it isn’t red, but in many species a Mr. Spock shade of bluish green. That’s because they don’t concentrate iron there, but rather vanadium, in the same row of the periodic table.

You don’t hear much about vanadium. Not even chemists hear all that much about it, at least not since the 1980s heyday of one of the Sharpless epoxidation reactions that uses it as a catalyst. (An old colleague of mine, Carsten Bolm, has been doing his best to revive that one). For one thing, it’s not a particularly abundant element – which led to questions about just how the tunicates were getting so much of it in their greenish blood. They had to be sequestering it from seawater, but that meant that they had to have some very efficient way to extract it.

Well, it turns out that they produce compounds now called tunichromes, unusual cyclic peptide catechol beasts that have a high affinity for vanadium. But finding and figuring out the structure of these things was a horrible undertaking by the Nakanishi group at Columbia, no strangers to ugly natural products. (He's now a professor emeritus, but I believe he's still hard at work).

The problem is, tunichromes are rather sensitive - all those phenols, y’know. They don’t like light (it’s pretty dim down in tunicate country), they don’t like heat (it’s not real warm there, either), and they don’t even like oxygen much, at least not the amounts found up here above the waves. And, as it turned out, they most definitely don’t like any form of silica gel, or any of the other solid supports used in chromatography. That ruled out HPLC, after what you have to gather was much heartbreak, because giving up HPLC means giving up an awful lot of separating power.

The group ended up using a technique you hardly see used any more, countercurrent chromatography. That requires a special apparatus where two immiscible solvents flow past each other, stage by stage. You’re extracting components from one into the other as things go along – it’s like regular chromatography, in a way, except you’re not using a solid powdery matrix to flow solvent over. You’re using another solvent. It takes, I believe, a delicate hand (I’ve never had the pleasure of doing it).

The sea squirt extract definitely got the kid glove treatment. Nakanishi’s folks ended up doing their countercurrent work with added t-butyl thiol in all their solvents, to guard against oxidation. That made things smell like the biggest natural gas leak in New York, I’m sure, but at least the smell was confined. That’s because they were doing all this in a cold room (a glorified meat locker), in the dark (with occasional darkroom lights when needed), and in inert-atmosphere bags and glove boxes. What a joy that must have been.

As it turns out, there's still a lot of controversy (PDF) about tunichromes and what they're doing in the live organisms. (That extends to the whole topic of metal concentration by marine organisms). When they were isolated, it looked like a good bet that they were the vanadium-concentrating substances, but later work has shown that they're not actually found in the same cells as the high vanadium concentrations. The whole reason that tunicates like vanadium so much is still something of a mystery - perhaps it's used in forming their characteristic outer tunic, and might serve to keep predators away.

But whenever things are going poorly for me in the lab, I consider that I could be sitting there in the reeking dark in my winter coat, hour after hour, grinding up dead tunicates and trying to keep the countercurrent apparatus working. Cheers me right up.

There's talk again about an idea that's been kicking around for some years: are drug companies shielded from liability after the FDA has approved their drugs for sale?

Obviously, the current answer is "Not at all": consider the lawsuits over Vioxx. But the decision by the Supreme Court in February in Riegel v. Medtronic has the idea being taken seriously again. That ruling seems to shield medical device companies from lawsuits over safety or efficacy after the FDA has signed off on those issues - as long as the device is the same, and used in the approved manner. And no, for the politically motivated among the readership, this wasn't some barely-realized 5:4 scheme from Justice Scalia; the decision went 8 to 1.

There's a roughly similar case before the court now, Wyeth v. Levine. At issue is the labeling and usage of Wyeth's histamine antagonist Phenergan (promethazine), with the suit being brought by a patient who was injured after the drug was used in a method warned against on the label. This one hinges on a federal/state dispute, though, as the petition for certiorari (PDF) makes clear:

"Whether the prescription drug labeling judgments imposed on manufacturers by the Food and Drug Administration pursuant to the FDA's comprehensive safety and efficacy authority. . .preempt state law product liability claims premised on the theory that different labeling judgments were necessary to make drugs reasonably safe to use".

This seems, if it goes Wyeth's way, as if it would keep various state jurisdictions from coming in with different liability claims, but the situation seems less stark to me if a state's standards were the same as the federal government's. Would this really pre-empt liability suits entirely? I'll let actual lawyers set me straight on that if I'm looking at it incorrectly.

There's another case that was granted cert. last fall, Warner-Lambert v. Kent, which could also have a bearing on the whole issue. This hinges on the approval (and later withdrawal) of the PPAR drug Rezulin (troglitazone), and whether Michigan state law on pre-emption of lawsuits is in conflict with the federal law. Again, I would have thought this one would probably be decided as a state-versus-federal issue, without extending to any sweeping thoughts on pre-emption in general. But that Medtronic decision makes a person wonder if the Court is in the mood for just that.

So, there's the background. Arguing will now commence on whether pre-emption is a good idea or not. I've thought for some time that all approved medications should be labeled as "investigational new drugs", and that everyone taking them agrees that they are participating in a post-approval clinical study of their safety and efficacy. (I suppose that's my own form of pre-emption). But there's room to argue if the FDA is ready to take on the full responsibility of drug approval, without the option of later redress in the courts if something goes wrong. (Counterargument: that's what they're supposed to be doing now. . .) And all of these schemes have to make room for new information turning up, or for outright fraud (which is most definitely in the eye of the beholder). Personally, I'm glad not to be a judge.

This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.

Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.

Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.

The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.

The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.

There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s