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
You'll have seen the news about the FDA safety warning on statins. The agency is warning that instances of hyperglycemia have occurred with statin use, as well as memory loss and confusion.
I'm really not sure what to make of this. On the one hand, these drugs have been through many, many large clinical trials under controlled conditions, and they've been taken by a huge numbers of patients out in the real world. So you might think that if these effects were robust, that they might have been noticed before now. But there are side effects that are below the threshold of even the largest clinical trials, and a patient population the size of the one taking these drugs is just where you might be able to see such things.
I lean towards the latter, and if that's true, then the agency's statement is appropriate. If these could be real effects in some patients, then it's worth keeping an eye out for them. One problem, though, is that hyperglycemia is rather more sturdy. You can measure it, and people don't really feel it when they have it. Memory loss and confusion are fuzzier, but they're immediately felt, so they're subject to more post hoc ergo propter hoc judgments. It's possible that more people will stop taking statins because of that part of the warning to cancel out the public health good that it might do otherwise.
The title of this one says it all: "Association of industry funding with the outcome and quality of randomized controlled trials of drug therapy for rheumatoid arthritis". Any number of critics of the drug business will tell you what that association is: we publish the good stuff and bury the bad news, right?
Well, not so much in arthritis, apparently. The authors identified 103 recent clinical trials in the area, over half of them industry-funded. But when it came to outcomes, things were pretty much the same. Trials from the three largest classes of funding (industry, nonprofit, and "unspecified") all tended to strongly favor the tested drug, although the small number (six) of mixed-funding trials ended up with two favoring and four against. The industry-run trials tended to have more subjects, while the nonprofit ones tended to run longer. The industrial trials also tended to have a more complete description of their intent-to-treat and workflow. As you'd figure, the industrial trials tended to be on newer agents, while the others tended to investigate different combinations or treatment regimens with older ones. But the take-home is this:
No association between funding source and the study outcome was found after adjustment for the type of study drug used, number of study center, study phase, number of study subject, or journal impact factor. . .
. . .Though preponderance of data in medical literature shows that industry funding leads to higher chances of pro-industry results and conclusions, we did not find any association between the funding source and the study outcome of "published" (randomized clinical trials) of RA drug therapies.
The one worrying thing they did find was a trend towards publication bias - the industry-sponsored studies showed up less often in the literature. The authors speculate as to whether these were trials with less favorable outcomes, but didn't have enough data to say one way or another. . .
The sponsors of the Research Works Act (Representatives Carolyn Maloney, D-N.Y., and Darrell Issa, R-California) have announced that they will not be bringing it forward. Elsevier's backtrack was indeed the sign.
Update: for the non-chemists in the audience who are wondering why one doesn't stroll in as advertised, check out what happens when you deal with the nastier end of fluorine chemistry. This new chemistry isn't anything like those examples - thank goodness - but it'll give you some idea of why we respect and fear the fluorine.
C&E News has an article on some of the recent fluorination methods that have been appearing in the literature. (Some of these have come up on this site here, here, and here).
These methods are all quite interesting (I've tried some of them out myself, with success), but what I also found interesting was the sociological angle that the article brought in. Organofluorine chemistry has not, over the years, been the sort of thing that one takes up lightly, for a lot of good reasons. Some of the real advances in the field have come from making it more accessible to more chemists. Very few people will use elemental fluorine other than at near-gunpoint, and some of the other classic reagents are still quite unfriendly, tending to leave cursing chemists swearing never to touch them again.
But making the field more open makes it, well, more open. And some of the people who've been there a while aren't quite sure what to make of the newcomers. They don't always cite the literature in appropriate depth, which is a real concern, and there can be a general feeling that they haven't paid their fluorine dues. (But the whole point is to keep people from paying those in the first place).
Since I'm not having to make my reputation discovering fluorination conditions, though, I'm just happy to deal with the results of all this work, both from the hardy pioneers as well as from the flashy new immigrants. These are useful reactions, and the rest of us are glad to have 'em.
I last wrote about the Molecular Libraries program here, as it was threatened with funding cuts. Now there's a good roundup of opinion on it here, at the SLAS. The author has looked over the thoughts of the readership here, and also heard from several other relevant figures. Chris Lipinski echoes what several commenters here had to say:
Lipinski notes that when the screening library collection began the NIH had little medicinal chemistry experience. "I was a member of an early teleconference to discuss what types of compounds should be acquired by the NIH for high-throughput screening (HTS) to discover chemical biology tools and probes. Our teleconference group was about evenly split between industry people and academics. The academics talked about innovation, thinking out of the box, maximum chemical diversity and not being limited by preconceived rules and filters. The industry people talked about pragmatism, the lessons learned and about worthless compounds that could appear active in HTS screens. The NIH was faced with two irreconcilable viewpoints. They had to pick one and they chose the academic viewpoint."
He says that they later moved away from this, with more success, but implies that quite a bit of time was lost before this happened. Now, we waste plenty of time and money in the drug industry, so I have no standing to get upset with the NIH about blind alleys, in principle. But having them waste time and money specifically on something that the drug industry could have warned them off of is another thing.
In the end, opinions divide (pretty much as you'd guess) on the worth of the whole initiative. As that link shows, its director believes it to have been a great success, while others give it more mixed reviews. Its worth has surely grown with time, though, as some earlier mistakes were corrected, and that's what seems to be worrying people: that the plug is getting pulled just when things were becoming more useful. It seems certain that several of the screening centers will not survive in the current funding environment. And what happens to their compounds then?
Courtesy of C&E News, here's an interesting look inside the Chinese labs of HEC Pharm, a company making APIs and generics. The facilities look good. I have to say, that's an awful lot of HPLC capacity, starting at 0:41.
The idea of company housing, though, is a bit harder to get used to. . .
It may well be. This morning comes news that Elsevier has dropped support for the RWA, which makes one think that they're feeling the pressure:
We have heard expressions of support from publishers and scholarly societies for the principle behind the legislation. However, we have also heard from some Elsevier journal authors, editors and reviewers who were concerned that the Act seemed inconsistent with Elsevier’s long-standing support for expanding options for free and low-cost public access to scholarly literature. That was certainly not our intention in supporting it. . .
While we continue to oppose government mandates in this area, Elsevier is withdrawing support for the Research Work Act itself. We hope this will address some of the concerns expressed and help create a less heated and more productive climate for our ongoing discussions with research funders. . .
You can smell the smoke from the brake pads, and hear the reverse gears engaging. Maybe now the American Chemical Society will make a public statement - I haven't heard anything from them yet, although their default position (as a member of the AAP) is to support it. (They supported a previous version of the bill in 2008).
Whoever's behind the Journal of Apocryphal Chemistry is trying to do everyone a good deed before we get into allergy season. After detailing the ever-more-stringent controls on the sale of pseudephedrine, they propose a synthetic route based on a more readily available starting material: methamphetamine.
A quick search of several neighborhoods of the United States revealed that while pseudephedrine is difficult to obtain, N-methylmethamphetamine can be procured at almost any time on short notice and in quantities sufficient for synthesis of useful amounts of the desired material. Moreover, according to government statistics, N-methylmethamphetamine is becoming an increasingly attractive starting material for pseudephedrine, as the availability of N-methylmethamphetamine has remained high while prices have dropped and purity has increased. We present here a convenient series of transformations using reagents which can be found in most well stocked organic chemistry laboratories. . .
Their route, based on a 1985 paper in J. Chem. Soc. Chem. Comm., is not exactly trailer-park chemistry, though. (I note that they have the reference a bit wrong as well; there was no plain J. Chem. Soc. in 1985). It involves a chromium carbonyl complex of the aryl ring, formation of a chiral lithium dianion, and oxidation of that with MoOPH, which would give you pseudephedrine after decomplexation. There's no way to tell if these reactions have actually been run, of course. Based on the literature precedent, it might work, although I'd be worried about maintaining the chirality of the dianion. (For what it's worth, the authors are also aware of this problem, and claim that the selectivity was unaffected).
Their larger point stands. I look forward to seeing more from this paper's authors, O. Hai and I. B. Hakkenshit. I see less interesting stuff in my RSS feed every day of the week.
Alex Tabarrok has an interesting post on the idea of patent protection for "independent invention". This would be for cases when two people or organizations independently arrive at the same thing:
In the minds of the public someone who infringes a patent is like a plagiarist or a thief–the infringer has copied someone else’s work or, even worse, stolen their intellectual property. In reality, patent infringement has very little to do with copying or theft. Here’s how I described what is probably closer to the paradigmatic case of patent infringement in "Launching the Innovation Renaissance":
'Two inventors, Kelly and Pat, work independently, neither aware of the other’s existence. Kelly patents first. Under the present law, if Pat wants to sell or even use his own invention, he must pay Kelly a license fee (!) even though Pat’s idea came from his own head and no other.'
If independent invention were uncommon this type of case wouldn’t be important but independent invention is very common. Classic cases include Newton and Leibniz with the calculus, Alexander Graham Bell, Elisha Gray and Johann Philipp Reis with the telephone, Ohain, Campini, and Whittle with the jet engine and so on. And if independent invention is common with great discoveries and inventions then it is surely much more common with ordinary innovations. As a result, it’s not surprising that most patent cases don’t even allege copying.
He proposes that "independent invention" be an available defense for claims of infringement. I agree in principle, but I worry that it would turn into just another way for people with the legal resources to tie up the system until their opposition gives in.
How would such a system affect drug discovery? Since we tend to spend a lot of time making sure that our molecules really are legally differentiable from the competition, I think that this would be less of an issue for us. But it's certainly true that some cases would arise. I personally have worked on a series of compounds (some years ago) that turned out to be the exact same series that a competitor was working on. The patents applications were filed within a couple of weeks of each other, and there were many compounds that overlapped. There are some areas where an independent invention defense could come in very handy (or be a major pain, depending on your relationship to the sharp end).
Stuart Cantrill has a post on one of those vast dendrimer structures - you know, those mandala-like things that weigh as much as a beer truck. He says that if you can draw the structure on his page in ChemDraw (or the like) in under three hours, you are clearly a wonder-worker.
He's asking on his Twitter feed for examples of the worst chemical structure anyone's had to draw, so I thought I'd throw the same question out to the crowd. You're going to have had to have lead an evil past life to be able to beat his dendrimer, though.
When I mentioned former FDA commissioner Andy Eschenbach the other day, I alluded to some other things about his approach that have bothered me. I thought I should follow up on that, because he's definitely not the only one. You may or may not remember this business from 2003, where Eschenbach wanted to set a goal for the National Cancer Institute to "eliminate death and suffering" from cancer by 2015. Here's what Science had to say at the time:
The nation's cancer chief, National Cancer Institute (NCI) director Andrew von Eschenbach, has announced a startling new goal in the battle against cancer. His institute intends to “eliminate death and suffering” from the disease by 2015. The cancer research community is abuzz over the announcement. Some say that however well intended, the goal is clearly impossible to reach and will undermine the director's credibility.
Von Eschenbach, who has headed the $4.6 billion NCI for a year, announced the 2015 target on 11 February to his National Cancer Advisory Board. He told board members that he did “not say that we could eliminate cancer.” Rather, he continued, his goal is to “eliminate suffering and death due to this disease.” NCI is working on a strategy to do that by discovering “all the relevant mechanisms” of cancer, developing interventions, and getting treatments to patients.
We have three years to go on that deadline, and it's safe to say that we're not going to make it. And that's not because we failed to follow Eschenbach's plan, because saying that you're going to figure out everything is not a plan.
Now, I'm actually kind of an optimistic person, or so I'm told. But I'm not optimistic enough to think that we can eliminate deaths from cancer any time soon, because, well, because I've worked on drugs that have attempted to do so. As has been detailed several times here (and many times elsewhere), cancer isn't one disease. It's a constellation of thousands of diseases, all of which end up by showing uncontrolled cell growth. Calling cancer a disease is like calling headache a disease.
But I'm operating on a different time scale from Eschenbach. Here he is in 2006, in The Lancet:
“Think of it”, von Eschenbach says, “for thousands of years we have dealt with cancer working only with what we could see with our eyes and feel with our fingers, then for a 100 years we've dealt with cancer with what we could see under a microscope. Now, we have gone in 10 years to a completely different level.” This new science “is going to change how we think, it's going to change how we approach things; it's going to change everything.”
. . .He points to the example of testicular cancer. The development of treatments for this cancer was a great success, von Eschenbach says, but one that “took decades of trial and error, one trial after another, after another, after another”. That hit-and-miss approach is no longer necessary, von Eschenbach says. Now, if 10% of patients responded to a treatment, he says, “you take the tools of genomics and go back, reverse engineer it, and ask: what was different about that 10%? Well, they had an EGF [epidermal growth factor] receptor mutation, ah ha!”
Ah ha, indeed. Here's more in a similar vein. The thing is, I don't disagree with this in principle. I disagree on the scale. No one, I think, knows how to eliminate deaths from cancer other than the way we're doing it now: detailed investigation of all sorts of cancers, all sorts of cellular pathways, and all sorts of therapies directed at them. Which is all a lot of work, and takes a lot of time (and a lot of money, too, of course). It also leads to a huge array of dead ends, disappointments, and a seemingly endless supply of "Hmm, that was more complicated than we thought" moments. I don't see that changing any time soon. I'm optimistic enough to think that there is a bottom to this ocean, that it's of finite size and everything in it is, in principle, comprehensible. But it's big. It's really, really big.
There are people who defend goal statements like Eschenbach's. Such things force us to aim high, they say, they focus attention on the problem and give us a sense of urgency. Taken too far, though, this point of view leads to the fallacy that what's important is to care a lot - or perhaps to be seen to care a lot. But the physical world doesn't care if we care. It yields up its secrets to those who are smart and persistent, not to the people with the best slogans.
I mentioned the fearsome memoirs of Max Gergel here, but not many people know that he wrote another volume. "The Ageless Gergel", out of print for who knows how long, is available here in PDF form. I have to note that it's even more rambling and formless than "Excuse Me Sir, Would You Like to Buy a Bottle of Isopropyl Bromide", and one also gets the impression that he used up a lot of his show-stopping anecdotes in the first book as well. I should also mention that the entire last section of the book is an account of a European vacation, during which no chemistry intrudes, and that the whole thing ends as if Gergel suddenly looked at his watch.
But there are some interesting chemical stories buried in there, and it's worth skipping through some parts to find them. This one's pretty typical:
I had been visiting Will at the plant in Elgin, South Carolina, and noticed that he smelled goaty. For that matter, the other workers seemed to have a goaty odor, too. I inquired the reason, and he took me to the source, an isolated section of the plant, which smelled horrendous. A large glass still, one that would have delighted a moonshiner in the old whiskey-making days was stinking up Hardwicke Chemical Co. and the surrounding farms. Now fatty acids have a rank odor smelling like rancid butter. The absolute worst member of the series is isovaleric acid. This smells like rancid butter with a soupgon of goat and old sneakers thrown in for good measure. As bad as it smells, the acid chloride derived from it is worse. It is so volatile that it will chase a visitor and leave its far from subtle mark. The odor is soap, water and Lysol resistant. This acid chloride reacts with mucous membrane so that while you are rendered ill by the obnoxious odor, the acid chloride is hydrolyzing with your perspiration as a reactant and eats away your lips, eyeballs and tongue. Hardwicke, committed to make this monster, was only too happy to find' Columbia Organic Chemicals Co., Inc., as a "farmout" and once more we were making something no one else wanted to make.
We had never had such a dreadful assignment. Anyone working with this "superstink" is branded and given a wide berth. No matter how amorous his spouse may be, passion crumples despite baths, Chlorox and Dentine. For a while we made isovaleroyl chloride at Cedar Terrace. It created pandemonium among residents who first sniffed each other, came to the plant to sniff us, and then sniffled to their lawyers.
Unfortunately, I can't quite put that acid chloride on my list of things I won't work with, because I have worked with it. But I can imagine that making it by the barrel would be a pretty repellent business, for sure. A 25-gram bottle was enough for me.
I wrote here about a very unusual dinitro compound that's in the clinic in oncology. Now there's a synthetic chemistry follow-up, in the form of a paper in Organic Process R&D.
It's safe to say that most process and scale-up chemists are never going to have to worry about making a gem-dinitroazetidine - or, for that matter, a gem-dinitroanything. But the issues involved are the same ones that come up over and over again. See if this rings any bells:
Gram quantities of (3) for initial anticancer screening were originally prepared by an unoptimized approach that was not suitable for scale-up and failed to address specific hazards of the reaction intermediates and coproducts. The success of (3) in preclinical studies prompted the need for a safe, reliable, and scalable synthesis to provide larger supplies of the active pharmaceutical ingredient (API) for further investigation and eventual clinical trials.
Yep, it's when you need large, reliable batches of something that the inadequacies of your chemistry really stand out. The kinds of chemistry that people like me do, back in the discovery labs, often has to be junked. It's fine for making 100mg of something to put in the archives - and tell me, when was the last time you put as much as 100 milligrams of a new compound into the archives? But there are usually plenty of weak points as you try to go to gram, then hundreds of grams, then kilos and up. Among them are:
(1) Exothermic chemistry. Excess heat is easy to shed from a 25-mL round-bottom flask. Heat is not so easily lost from larger vessels, though, and the number of chemists who have had to discover this the hard way is beyond counting. The world is very different when everything in the flask is no longer just 1 cm away from a cold glass wall.
(2) Stirring. This can be a pain even on the small scale, so imagine what a headache it is by the kilo. Gooey precipitates, thick milkshake-like reactions, lumps of crud - what's inconvenient when small can turn into a disaster later on, because poor stirring leads to localized heating (see above), incomplete reactions, side products, and more.
(3) Purification. Just run it down a column? Not so fast, chief. Where, exactly, do you find the columns to run kilos of material across? And the pumps to force the stuff through? And the wherewithal to dispose of all that solid-phase stuff once you've turned it all those colors and it can't be used again? And the time and money to evaporate all that solvent that you're using? No, the scale-up people will go a long way to avoid chromatography. Precipitations and crystallizations are the way to go, if at all possible.
Reproducibility. All of these factors influence this part. One of the most important things about a good chemical process is that it works the same flippin' way every single time. As has been said before around here, a route that generates 97% yield most of the time, but with an occasional mysterious 20% flop, is useless. Worse than useless. Squeezing the mystery out of the synthesis is the whole point of process chemistry: you want to know what the side products are, why they form, and how to control every variable.
Oh yeah. Cost.Cost-of-goods is rarely a deal-breaker in drug research, but that's partly because people are paying attention to it. In the med-chem labs, we think nothing of using exotic reagents that the single commercial supplier marks up to the sky. That will not fly on scale. Cutting out three steps with a reagent that isn't obtainable in quantity doesn't help the scale-up people one bit. (The good news is that some of these things turn out to be available when someone really wants them - the free market in action).
There are other factors, but those are some of the main ones. It's a different world, and it involves thinking about things that a discovery chemist just never thinks about. (Does your product tend to create a fine dust on handling? The sort that might fill a room and explode with static electricity sparks? Can your reaction mixture be pumped through a pipe as a slurry, or not? And so on.) It looks as if the dinitro compound has made it through this gauntlet successfully, but every day, there's someone at some drug company worrying about the next candidate.
Here's a huge review that goes over most everything you may have wanted to know about what's called "rational drug design". The authors are especially addressing selectivity, but that's a broad enough topic to cover all the important features. (If you can't access the paper, here's a ke