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: firstname.lastname@example.org
I didn't watch John Kerry's speech tonight. I'll watch a political speech made to a potentially hostile or sceptical audience (like the State of the Union) but not one made to an adoring throng, either throng. Life is too short.
But I've had some e-mail pointing out that Kerry whipped out a line about drug prices, which I presume was an applause-getter:
"Under our plan, Medicare will negotiate lower drug prices for seniors. And all Americans will be able to buy less expensive prescription drugs from countries like Canada."
Of course, the law as it stands forbids any drug company from offering anyone a lower price than they offer Medicare. Ask Schering-Plough how that one works. But what Kerry is talking about is modifying the latest Medicare drug benefit, to allow the federal government to directly negotiate drug prices. My industry put up a serious battle to keep that from happening, and it's no secret why. This is a direct route to Federally mandated drug price controls. If you think that those are a good thing, then you like that idea - if not, you don't.
And as for importing drugs from Canada, well, I'll resist the temptation to start turning purple again. But I took Kerry's suggestion to go to his campaign website for more details:
"The Kerry-Edwards plan will reduce prescription drug prices by allowing the re-importation of safe prescription drugs from Canada, overhauling the Medicare drug plan, ensuring low-cost drugs, and ending artificial barriers to generic drug competition."
Now that word "safe" is an interesting one to drop in there. As many readers know, Congress has already passed a law making it legal to reimport drugs from Canada - but only if the FDA certifies their safety. And that the agency has refused to do, saying they don't have the resources to make such a guarantee. Is Kerry planning to give the FDA whatever it might need to go ahead and make the call? Or is this an escape clause to allow the status quo to prevail?
Well, if that Medicare idea comes true, it could be a moot point. There won't be much need to import drugs from Canada if we become Canada, will there?
As I mentioned yesterday, I've been spending the last couple of days working on salt forms of one of our compounds. Even folks who slept through one semester of general chemistry may remember that an acid plus a base gives you a salt, which is just what I've been doing. Most of the compounds we work with have a basic nitrogen atom in them somewhere - medicinal chemistry would grind to a halt without basic nitrogens - so to form a salt you add an equivalent amount of some acid.
Once or twice in my career I've batted from the other side of the plate, working with acidic compounds and making a salt by adding a base. There are some therapeutic targets where only acidic compounds seem to work, but I haven't spent as much time on those. Actually, acidic compounds aren't as much trouble. They seem to behave a little better in their original form than the strongly basic ones do, partly because they're not suddenly being jerked over to the other end of the pH scale when they hit the stomach, and partly because they can deal with a whole different set of uptake and transport systems.
The reason you go to all this salt trouble is because the salts are often easier to dissolve and dose than the free bases. Often the situation is even worse than that: the free base is nearly impossible to dose, and a salt form is your only way out. There are a limited number of things you can dissolve your compound in if you're giving it to a mouse or rat every day. (The rats are a bit more resilient, as a rule.) Water would be ideal, but I'm not sure if I've made half a dozen things in the last fifteen years that would just dissolve in straight water.
A common (and reasonably innocuous) additive is polyethylene glycol, known in the trade just as "peg." (I often come away from formulation discussion humming Steely Dan.) I'm trying to get these compounds into half-and-half PEG/water, and anything will be an improvement over the lumpy-gravy suspensions that we're getting now. Suspensions aren't bad per se: a good one, which has the pearly look of an opaque shampoo, is a fine dosing method. But they're not all created equal, and they're harder to generate reproducibly. The problem with dosing the oatmealy ones is that they give you lower blood levels than you expect for a given amount of compound, and the levels tend to vary along with the (unreproducible) size of the lumps. The experiments are nearly worthless.
So what sorts of acids do we use? The most popular is good ol' hydrochloric. At least half the pharmaceutical salts on the market are HCl-derived. Then there are salts from organic acids (maleate, citrate, fumarate, gluconate), other mineral acids (sulfate, phosphate), and some mixed breeds like methanesulfonate. Those probably cover 95% of what's out there.
The ideal salt is stable, powdery, free-flowing, and doesn't turn into a goo by soaking up water from the air. You find that elegant substance in the least elegant way possible, because there is absolutely no way to tell which of these is going to be the best. There are some rank-order decision tree charts that people use, but they're departed from as often as they're honored. My chosen field, once you get the gift wrap off of it, is about as empirical as they come.
You know, it does feel odd not to be writing anything about the political season, what with all the conventioneering going on. But world events, for the most part, sort of wash over and around this blog, which is a decision I made back in my early days. Political opinions are piling up unsold in every market stall, but who offers commentary on chemistry?
Of course, there's always the question of market size. A single-subject site is never going to pull in the traffic of the big generalist ones, unless the subject is something rather more stimulating than organic chemistry (if you know what I mean and I think you do, as Joe Bob Briggs used to say.) But I've been encouraged by the responses I've had from people completely outside the sciences who've enjoyed visiting them by reading here.
Still, knowing that I have a widely mixed audience makes it tricky sometimes. There are some subjects that are harder to cover, and there are jokes that are hard to make. For example, I guarantee that every organic chemist will at least smile at a phrase like, oh, "plutonium enolate." But that's not going to make 'em spill their beer down at the comedy club, unless they're spilling it on the person trying to tell the joke.
So I'd like to take advantage of this slow news period to ask people if there are topics they'd like to see more (or less) of: current pharma news, stock market stuff, lab stories, med-chem background, purple-faced rants about price controls? Comment below, or feel free to e-mail me.
I hesitate to mention topics that I'm planning to post on, because it seems that I never get around to them, but the future should hold pieces on combination drugs (boon or gimmick?), salts and why I'm making a bunch of them right now, and (if I can summon the energy) a whack at Martha Angell and her recent NY Review of Books broadside against my industry. She has a book coming out this fall, and naturally I can hardly keep my enthusiasm from just foaming up all over the place. Sheesh.
Back before my vacation, I mentioned the problem of judging how long a drug project should be allowed to run. You have to call a halt eventually, because it's very rare for a project to finish of its own accord - by which I mean "arrive at a conclusion that no one can argue about or wish to change."
That goes for either kind of conclusion. It's difficult for a project to fail so conclusively that no one wants to take just one more crack at it. Maybe you haven't been dosing the right way, or in the right formulation, or in the right sort of animal. There's always another series of compounds to try; success could be just around the ol' corner. Sometimes it is - there are some tremendously successful drugs that nearly died several times in preclinical development, until someone found a way to defibrillate the project and make it get off the floor.
I have managed to totally kill one at least once in my career, though, when we showed that there was an insurmountable side effect problem caused by the exact same enzyme that we were already targeting. Turns out that it does two different things in different tissues, and any inhibitor is thus going to run into the same problem. Not a thing you can do about it.
And on the successful side, it's unusual for a compound to do everything you want it to - potent, selective, good oral dosing, no side effects, cheap and easy to make on large scale. Most of the time, you're faced with an array of compounds, each of which might do the job, each with a different pattern of potential defects. If you'll only accept a perfect compound, you'll spend years crawling up the asymptotic curve, spending ever more money to fix ever smaller problems. You just have to call a halt at some point and declare that what you have is good enough. (This is no doubt sounding very familiar to the engineers out there.)
But when do you reach that point? I wish I had a general answer. (If I had one, I'd probably be writing this from my private island estate.) Clearly, for a bigger potential payoff you should be willing to spend more money and take more time. A potential breakthrough therapy should get several chances to come back from the grave, which is why (as I mentioned above) there's a disproportionate number of such stories among the blockbuster drugs.
But having your project nearly die doesn't mean that it's going to be a winner; that's not how you join that club. The sixth-on-the-market therapy for toenail fungus could just as easily be an exciting development story for those involved; it doesn't mean that it was worth doing.
Someone came to my lab today to borrow some thiophenol, a request that made me think of something that happened in my first summer of undergraduate research - twenty-two, gulp, years ago. Now, thiophenol is not known as a great inducer of nostalgia. Like the other small-molecule sulfur compounds, it reeks without letup. It's a major part of the smell of burning rubber, so if you can imagine that concentrated and put into a bottle, you've got a pretty good idea. It's distinctive.
I was using this cologne as a starting material, reacting it with sulfuryl chloride, which is another reagent that no one is going to dab behind their ears. It's a reactive chlorinating agent and a fairly strong oxidizer, and it'll make you shake your head and snort if you come across its fumes, for sure. The two of them together make an eyebrow-raising mixture - I was exiled to a lab at the other end of the building while I ran this one, just because of the potential smells.
Heating this brew gives you phenylsulfenyl chloride, a red oil which combines the foul properties of its parent compounds. You distill the stuff out of the reaction, cap it up, and store it in the cold. I think it's too reactive to be an article of commerce; you have to make it fresh. And make it fresh I did, even though everything around me smelled as it had been dead for weeks. In the freezer with the stuff for the weekend (we didn't work grad-school hours at my all-undergraduate school, not even in these summer research programs.)
Monday morning I went down and picked up the flask. Hmmm. . .no longer a red oil. Odd. The stuff had changed to a pale yellow solid, which didn't seem right. I wasn't sure of the compound's freezing point, but the color change alone made me wonder. I stood there puzzled for a minute or so with the tightly stoppered flask in my hand, holding it up to see what I could make of the stuff. And then, with a loud gunshot bang, the top of the flask exploded in my hand.
I jumped straight up in the air, flinging away the lower part of the flask that I was still holding. I came down on the balls of my feet, in a fight-or-flight stance, looking around wildly. I didn't feel as if I'd been injured, but I'd never had anything blow up while I was holding it, either, so who kenw? After a second or so I looked down to see if I was OK. And weirdly enough, I was. I can't imagine how I managed not to pick up some glass shrapnel, at least - perhaps even at that early point in my career I had enough sense not to point the neck of a round-bottom flask toward me. My hand was fine - I kept flexing my fingers in wonderment. After a minute of two of stalking around the room, shaking and gibbering, I started looking around to see what had become of the chemical.
I found it about ten feet away, a lens-shaped piece of light yellow stuff, molded smooth by the inside of the flask. Whatever it was, it wasn't melting again, and it sure wasn't phenylsulfenyl chloride. We figured out what it was pretty quickly, but I think I'll leave its identity as an exercise for the technical portion of my readership - guesses to go in the comments below. If you get it right, you'll know why it blew up, too!
Continuing on the latest issue of the New England Journal of Medicine and its articles on cancer therapies, there's the Perspective article, from Deborah Schrag at Sloan-Kettering, which points out that:
"In the wake of the optimism generated by recent trial results, patients experience sticker shock when they encounter the prices of chemotherapy drugs. Physicians find themselves in the undesirable position of having to help patients make decisions about whether the potential clinical benefits warrant the financial strain that even the copayments for these medications may create."
I don't doubt it. She has a chart for a typical patient's eight-week therapy on various regimes. Drug costs for the classic fluorouracil-based therapies will run from $60 to $300 for that period. Throw in irinotecan, the standard since the mid-1990s, and you're looking at about $10,000 for the same eight weeks. An Avastin-based treatment will double that, and an Erbitux-based one will triple it. And those are just wholesale drug costs; they neglect support, labor, wastage, and so on. Avastin and Erbitux are harder to store and administer, so their costs will be still higher. And even if you take the statistics in the latest paper at face value, median survival is increased by less than two months with Erbitux. That brings us to a terrible question: how much are those two extra months worth, and who should pay for them? Everyone's trying to offload that decision onto someone else, and I don't blame them a bit.
We're back to where I was discussing this issue a few weeks ago. As I said then, I think that the solution is that many people won't (and shouldn't) take these therapies, because they're just not worth it. But that's a hard thing to convince someone of, and I'm glad that I don't have to try. My attempt to pass the buck is to point out that none of us in the industry is trying to develop a hugely expensive drug that only prolongs survival by a couple of months - that's just how the damn things come out after we've already spent the time and money. We're trying to hit home runs over here, but the pitching is too strong for us.
The article gets its shots in at the drug industry, though:
"Early scientific work that led to the discovery of bevacizumab (Avastin) and cetuximab (Erbitux) was financed with federal dollars. The pharmaceutical industry translated these fundamental insights into the development of commercial products. The rising stock prices of the publicly traded companies that manufacture these drugs reveal that, development costs notwithstanding, the risk-adjusted return on pharmaceutical products is very high indeed. The drug costs that support these stock prices threaten to overwhelm our ability to pay for health care."
Well. . .let's dispose of those in order, then. The first part is the old drug-companies-rip-off-NIH canard. Allow me to point out that no academic labs were attempting to turn antibodies against the growth factors receptors into new drugs, so why is industry to blame for trying? "Translating fundamental insights into the development of commercial products" is exactly what the drug industry does. It's very hard to do, it's very risky, and it costs a hell of a lot of money. You have a problem with that? If Dr. Schrag believes that she can do it more cheaply and efficiently, I invite her to raise the money and come on down and try it. Many people have done just that, and it's an education, all right.
And as for drug costs overwhelming "our ability to pay for health care", has Dr. Schrag considered that the total contibution of drug costs to health care is below 20%? Isn't there any overwhelming being down by the rest of the business, or are they just standing around in awe of our mighty powers?
And let's see. . .the rising price of the stocks, yes. Please note that I think that Imclone's stock is already too high. As high as Erbitux's cost is, I still don't think it can support Imclone's current price. I think that Bristol-Meyers Squibb overpaid for their share of the drug, and I'm not sure they're going to end up with much of a return. Note also this post about the amount of money that the biotechs have lost over the years - on average, biotech investors have lost money and they continue to lose it. For some years now, anyone investing in the stocks of companies I've worked for has been taking a bracing bath indeed. Believe me, although there are some good investment opportunities, the drug industry only looks like a money machine to the unwary.
Since I last wrote about Imclone, the stock has had a rather difficult time. That's largely the fault of the Imclone fan club: Erbitux sales have exceeded some of the responsible projections, but still haven't caught up with the fantasies of some of the stockholders.
And now comes a study in the New England Journal of Medicine (about as high-profile a place as you can publish this kind of thing) confirming that Erbitux does shows activity in late-stage colon cancer, when added to the standard irinotecan therapy. Good news, eh? But in the end, the publication may do as much harm as good to Erbitux's prospects, because the same issue has a rather sceptical editorial comment on the study, and a longer perspective piece on the costs of such treatments in general. (Full text isn't available to nonsubscribers - the beginning of the editorial is here and the beginning of the Perspective is here. I'm going to cover that one in the next post for Monday; it makes this one too long and unwieldy when they're combined.)
The editorial, from two physicians at the Mayo Clinic, isn't kind. It's enough to make you wonder why they accepted the study for publication in the first place: ". . .the findings clearly support the notion that interfering with EGFR signaling can overcome the resistance to irinotecan. Nevertheless, the appropriateness of the authors' reporting methods warrants discussion." They point out that the trial was statistically underpowered to detect some clinically meaningful differences, and question whether the reported response rate can justify using Erbitux as a monotherapy. The authors attempted to test the patients for EGFR expression, but it's unclear if they did this in the right way (it's not as simple as you'd think.)
Even if you take the statistics as they are, Erbitux added less than two months to the lives of patients, on average, compared to the current standard of care. The authors' verdict: there may well be clinical settings or treatment regimens where Erbitux is more useful in such colon cancer patients, but we don't know what they are yet. The addition of Erbitux to the list of treatments, they say, "must be tempered by the small advances that it offers in terms of the time to progression and the response rate and its uncertain effects on survival. . ." Not to mention the cost, which we'll take up in the next post.
In light of all this, I'd like to take a moment to address the Imclone-boosting stock cult, those few of them who might have read this far, anyway. Get out. Take the money and run. The alarm bell has sounded, and more than once. If you bought Imclone when it was in the dumper, you've had a great run. Celebrate and cash in! But if you bought it when I was ranting on the subject back in late June, you're in the red, and I fear that it's going to be even worse in the long run. Flee!
Continuing on the theme of unexpected toxicity landmines, I wanted to take a look at a highly anticipated obesity drug from Sanofi. Rimonabant is a small molecule antagonist of the CB-1 receptor, and it's been getting a lot of press - both for its impressive efficacy and for its mechanism of action. The "CB" in the receptor name stands for "cannabinoid", and the drug blocks the same receptor whose stimulation causes the well-known food cravings brought on by marijuana.
Interestingly, blockade of this receptor not only seems to affect appetite, but also seems to help with cravings for nicotine. As you can imagine, the market potential for the drug could be immense (and as you can imagine, other drug companies are chasing the same biological target, too.)
But what else does an antagonist do? The receptor has, no doubt, several functions in the brain (all the CNS receptors do multiple duty), and it's scattered around in the nerves and other tissues as well. There have been a couple of reports that bear watching. A team of researchers (German/Italian/US) reported earlier this year that the CB-1 receptor seems to be involved in inflammation of the colon. Mice with the receptor knocked out show great susceptibility to chemical irritants in the gut, and (more disturbingly) the same effect was seen in normal mice treated with a CB-1 antagonist. The authors suggest that CB-1 may be involved in diseases like Crohn's and irritable bowel syndrome, but antagonists would, if anything, make the problem worse.
That's bad enough, but there's a potential disaster that just showed up last month. The authors report that a patient of theirs suddenly came down with multiple sclerosis after having been a subject in a rimonabant trial. Now, there's no way to prove causation, as they freely admit, but there's some evidence that CB-1 has a neuroprotective effect under normal conditions. So blocking its actions might conceivably expose neurons to damage, and when you combine that with the above potential role in inflammation, you have something that you should keep an eye on.
No one can say how this will play out. The most likely outcome is the best one - that the drug isn't associated with MS or Crohn's. After all, it's been through some extensive trials, and Sanofi still seems confident - which, believe me, they wouldn't be if a good fraction of the participants had come down with irritable bowel syndrome, much less multiple sclerosis. But there's another possibility, that the trouble will only show up in some patients under some conditions, and it might be rare enough that you won't see it until it gets out into the general population. There's just no way to run a clinical trial to nail down the statistics on, say, a one in 50,000 side effect. You'll never see it coming.
That MS report in particular must have the Sanofi people a bit worried, and I'm sure it has the attention of the other players in the area, who will be glad to let Sanofi go out and be the lightning rod in case anything bad happens. Odds are that it won't, but there are no sure things, not with this drug or any other. Honestly, it's years before you can relax in this business, if you ever do. Good luck, guys.
The PPAR family (known in the US as alpha, gamma, and delta, for obscure historical reasons) is one of those biological jungles that keep us all employed. They're nuclear receptors, and thus they're involved in up- and down-regulation of hundreds of genes. Like most of the other nuclear receptors, they do that by responding to small molecules, which makes the whole class a unique opportunity for medicinal chemists.
Normally, we can't do much about gene regulation, because it's all handled by huge multicomponent protein complexes, terrible and unlikely candidates for intervention with our drug molecules. But when the whole thing is set off by binding of a small ligand, well, that's all the invitation we need. To pick a well-known class of small ligands, the best-known members of the NR superfamily are the steroid receptors, which should give you some idea of how powerful these things can be.
For their part, the PPARs are all major players in cellular energy balance and fuel use, the handling of fatty acids and other lipids, the generation and remodeling of adipose tissue, and similar things. That lands them squarely in some very important therapeutic areas such as diabetes, obesity, and cardiovascular disease. But more recently, it's become clear that they're also involved in things like inflammation and carcinogenesis, which brings in another huge swath of the drug industry. Every large drug company is working on them, for one indication or another. Heck, you could run an entire drug company on nothing but PPAR-related targets, that is, if you weren't terrified by the insane risk that you were taking.
Problem is, the biology of nuclear receptors is powerfully complex and murky. We know a lot more about them than we did five or ten years ago, but it's obvious to everyone in the field that we still have very little idea of what we're doing. Take a look at the three PPARs: there are two diabetes drugs on the market that target PPAR gamma (Avandia and Actos, aka rosiglitazone and pioglitazone), but no one has been able to get anything significantly better or safer than either of those. PPAR alpha is supposed to be the way an old class of lipid lowering drugs (the fibrates) work, but no one's really sure that they believe that. Several companies have been working on PPAR alpha drugs for a long time now, and nothing's made it deep into the clinic yet, which isn't a good sign. And no one really knows what PPAR delta does - it seems to have something to do with lipid levels, and something to do with wound healing, and something to do with colon cancer. The clues are rather widely scattered.
I've mentioned that several companies have been working on combination diabetes drugs that would hit both PPAR gamma and alpha. The idea is that they'd do all the glucose lowering of a gamma-targeted drug, and lower lipid levels at the same time - a worthy goal for the typical overweight Type II diabetic patient. But Novo Nordisk, racing along with a compound they licensed from India's Dr. Reddy's (the evocatively named ragaglitazar) hit the banana peel when long-term rodent testing showed that the compound was associated with bladder cancer. Then Merck, which had a compound from Japan's Kyorin in advanced trials, pulled it when another rare cancer showed up in long-term rodent studies. Screeching halt, all over the industry.
Now the FDA has jumped in, with a requirement that any new PPAR drugs go through two-year rodent toxicity testing. That's an unusual requirement, but (as the two examples above show) it's something that companies were already doing on their own initiative. Bristol-Meyers Squibb and AstraZeneca have already done theirs, for example, and are plowing on.
The feeling has been: no one really knows what to expect from new PPAR compounds, so you'd better test the waters extensively. The thought of putting a compound on the market that turns out - years later - to be linked to increased risk of something like bladder cancer is enough to give everyone nightmares. I should mention that nothing bad has been seen from the two marketed PPAR gamma compounds I mentioned. But everyone remembers that there was another one, troglitazone, the first to market and the first to be pulled. It showed liver toxicity, but that seems to have been compound-related rather than mechanism-related.
Here's an article from Forbes on the subject, one of the few outlets that covered this story in any detail. It's pretty good, although it glosses over a lot of things. For example, the article quotes Ralph DeFronzo of UT-San Antonio saying that the fibrate drugs have been targeting PPAR-alpha for years, so why is the FDA worried about that subtype? What that ignores is that the fibrates are actually very weak drugs at alpha, which is why I mentioned the doubts people have about the whole mechanism. The drugs being developed now are thousands of times more potent. And look at the alpha-gamma combinations: why did all the trouble start only when alpha was added to the mix?
Well, we've got plenty of work to do. Unraveling the biological effects of the PPARs is going to take many, many years. And we're going to have to do it in rodents, in dogs, and in humans, at the very least - all the major species that are tested for toxicity. We already know about some significant differences between the species in the way that these nuclear receptors work. Will these cancer problems be another one? Are humans going to be just fine? Or will we react in even worse ways, given enough time? We just don't know. Everyone's holding their breath, waiting to see what comes next. . .
I've spaded through the heap of e-mail at home and at work, and I'm ready to get going again. My lab is on another new project, which means that I need to clear my desk of the piles of notes and papers from the last one. Some of those will go into the permanent files, while others will go into the handy recycling box. Rather more of the latter, actually.
Here comes another class of molecules that I've never worked on before, but to judge from the torrent of hits that I get from literature searches, they've had plenty of admirers. It's the exact situation I spoke about recently: we've got to carve out some patent space and hope that it overlaps with the space of active compounds. There are whole classes of structures that we're probably not even going to bother looking at, because it's clear that we can't own a position there.
Really significant effort goes into such contortions. I can't imagine what a pharmaceutical world without chemical intellectual property would feel like, but it sure would be less complex for people like me. Mere anarchy would sure enough be loosed: just make whatever you want to, and go where the assays tell you. But I can't imagine how you'd make it pay, either, which is why we're in the world we're in.
Qetzal makes a good point in the comments to the previous post: "fail quickly" is fine, but when are you sure that you've failed? It's a real problem. Medicinal chemists like me are notorious for always having another chemical series to try, another set of modifications that just might do the trick. We can go on for years, and sometimes we do.
The trouble is, sometimes you go on for years and get squat, and then everyone involved resolves to never let a project go on for more than eight months before pulling it. Other times things lurch along until a sudden breakthrough three years in, leading to a zillion-dollar hit. Then everyone involved resolves to never kill a project after just two years, because you never know.
I'll take up this subject - though I doubt I'll solve it! - when I get back from vacation. This will be the last post until next weekend. I can't say that I'll be thinking about the problems of the drug industry for the next few days, but perhaps some sections of my brain will be on the case.
Next week I'll be on vacation, and this week I find myself flogging the chemistry databases. We're looking at a new series of compounds with some interesting activity, and they're easy to make. That's the problem.
They're so easy to make that everyone has made them. That means trouble, because there's so much prior art (and so many potentially interfering claims) that we'd have a difficult time getting a patent position. There are quite a few popular structural classes with this problem: piperazines, indoles, and imidazoles have been trampled flat, for example, and try getting (for example) a claim in some of the benzofuran compound space that Lilly has staked out. Not fun.
So we're looking to change the inner parts of the structure in some non-obvious way and thus stake out a position with some elbow room in it. It's not easy - for one thing, things are to the point that some of the obvious paths to elbow room have already been worn out a little. And you don't want to come up with new ones that are going to take fourteen steps to make, either. That's because it's unclear whether the interesting activity that got us here will persist once we start chopping and rearranging.
Often it doesn't. You feel like a real idiot - even if you aren't - when you spend a lot of time on a series like that and none of the compounds are active. And you feel as if you've wasted our time, because you have. "Fail quickly" is one of the basic mottos of medicinal chemistry.
July 4th here: my two small children are splashing around in an inflatable pool out in the yard while I check the whole pork shoulder that's been cooking since about seven in the morning. More soaked hickory chips go in. (Where I grew up on the Delta, you can spot the barbecue restaurants because they always look as if they're on fire.) I'll have it with beans and my wife's cole slaw, and there's watermelon and homemade strawberry ice cream for dessert.
My wife and her mother are drinking tea out under an oak tree, beyond the kids's splash radius. Next to them, on a green picnic table, I've set up my old microscope, a medical student model that my parents gave me when I was ten. Earlier we were looking at some pond droplets, my son and daughter dripping with pool water as they peered at rotifers and nematodes.
My son has already announced that he wants some scissors when we go back inside, because he wants to cut some of the signatures out to keep from the newpaper's annual full-page reproduction of the Declaration of Independence. He and his sister especially like John Hancock's, of course, and the smart remark he made when he signed it. This year I pointed out Ben Franklin's signature, and related his line about all hanging together or all hanging separately, but I could tell that it didn't register - as it well shouldn't, but I couldn't resist.
They haven't grasped that people back then fought under terrible conditions - aren't they all - to be rid of a king and what he represented. And they don't realize how strange it was for a people to throw off the rule of a king and then, somehow, to avoid ending up under his replacement. (Meet the new boss!) George Orwell famously said that if you wanted to imagine the future, to picture a boot stamping on a human face, forever. But that's an even better summary of the past. Just look at it.
What's even stranger is that for over two hundred years we've continued to avoid all the kings, emperors, sultans, First Citizens, mullahs, all the other graspers and grabbers who long to be at the thick end of the whip. They're in long supply, unfortunately. My wife and her mother, out there in the yard, are both exiles from Iran. They can tell you all about it, starting in the days of the Shah. Then they'll go on to the days after the Shah's portraits were crowbarred down and another loser's stuck right up on the same spot so the paint job wouldn't look funny.
It's safe to say that none of us here in the back yard have any desire to be part of a restored Caliphate. The fellows who want to be in charge of it don't look like the sort who would look kindly on this scene, and not just because of the pork shoulder. And there are plenty of others who would find it necessary to shape things up around here if they were in charge, for that matter.
That'll serve as a test, then: anyone who'll leave us to our own devices this July Fourth - those people are the ones welcome here, strangely enough. If you don't give a damn, then sit down and have some strawberry ice cream. But if you think it's your duty to set us straight, then I've got a section of the newspaper for you to study. It has some holes cut out of the bottom part, but the main points are still there.
I wanted to emphasize a point I made yesterday, about how far removed the research organization is from the sales force in a drug company. I'm not backing away from them, just pointing out that we're at completely opposite ends of a company's functions.
By the time a drug gets into the hands of the sales team, it's been many years since anyone in my area ever worked on it. Several members of the original team have usually left the place completely by that time, and are working for the competition when the drug they helped discover actually makes it to market. The ones who are still there have worked on several other projects by then, and would be hard-pressed to recall all the details of the series of compounds that led to the marketed one. Did we ever try to put a fluorine at that position? Well, yeah, I thinkso. . .didn't so-and-so try that? But they left three years ago, you'd have to go dig through their notebook. . .
It's not like there's no pride in ownership. Everyone in research knows who discovered and worked on the drugs that actually make it all the way to market (partly because there are so few!) It's just that there's such a long lag time between the work we do and the commercial life of the drug. That's why the sales force doesn't have much to say to the research labs, and vice versa. Nothing we're doing can possibly affect their lives in under seven years, and most of the things we're doing will fail and disappear long before then.
The marketing practices mentioned in the last posting sound a lot like radio-station payola - paying to get a song on the air. There was an interesting defense of this practice mounted recently over at Marginal Revolution (see the first three postings here.
Is there a difference in this case? (I mean, short of the "we're-talking-about-people's-lives-here" argument, which can be valid but ends things before you have a chance to do any potentially useful thinking.) I think there is, and it has to do with market efficiency.
Whether a song becomes a hit or not is based on a relatively quick aesthetic call by a large audience: "I like that." The pro-payola argument (or at least the non-anti-payola one!) is that you can't force a song to be a hit by paying for airplay - all you can do is pay enough to give it a chance to become one. There are historical examples of songs and artists that likely wouldn't have had a chance without someone opening their wallets.
But paying doctors to prescribe certain drugs is a different sort of market perturbation. For one thing, there's not such a good feedback mechanism as there is with listener choice. It takes a while before you can tell if most medications are working or not, days or weeks. And even then, it may not be apparent to the patient. Blood pressure therapies don't make you feel much different at all, even when they're lowering life-threatening hypertension. And most chemotherapy (to pick an extreme case) makes you feel absolutely worse, immediately and continuously, even if it's managing to put your cancer into remission.
And songs are more clearly differentiable, making their market more efficient. Listeners can pick out a new song by an established artist quickly, and if it's someone they've never heard before, they'll notice that, too. But the differences between, say, the different statins are more subtle. You won't feel your HDL increasing a bit more with one of them versus the other - heck, unless they look at a large statistical sample, physicians won't notice that, either. And there's the large question, in this case and others, of whether that real difference is enough to have a real clinical effect. No one's in doubt for very long about whether a song has accomplished what it's trying to do.
In radio payola, you're trying to seed a large market and hope that something will then take off through the free choice of the consumers. But who are the consumers in the prescription drug market? There are areas where direct-to-patient marketing works, in which case it's clear that the patients are regarded as the real consumer. The hope is that they'll storm their doctors offices clamoring for the latest therapy (much to the irritation of the doctors involved, I think!)
But in many other fields, it's the physician that's clearly the consumer and the target of advertising. Schering-Plough appears to have been paying for their interferon to be prescribed for hepatitis patients, among other things, and there's never been much (any?) direct-to-patient advertising there. One physician can write for a large number of patients, so the temptation for well-targeted payola is strong. And wrong.