Moore's Law: number of semiconductors on a chip doubling every 18 months or so, etc. Everyone's heard of it. But can we agree that anyone who uses it as a metaphor or perscription for drug research doesn't know what they're talking about?

I first came across the comparison back during the genomics frenzy. One company that had bought into the craze in a big way press-released (after a rather interval) that they'd advanced their first compound to the clinic based on this wonderful genomics information. I remember rolling my eyes and thinking "Oh, yeah", but on a hunch I went to the Yahoo! stock message boards (often a teeming heap of crazy, then as now). And there I found people just levitating with delight at this news. "This is Moore's Law as applied to drug discovery!" shouted one enthusiast. "Do you people realize what this means?" What it meant, apparently, was not only that this announcement had come rather quickly. It also meant that this genomics stuff was going to discover twice as many drugs as this real soon. And real soon after that, twice as many more, and so on until the guy posting the comment was as rich as Warren Buffet, because he was a visionary who'd been smart enough to load himself into the catapult and help cut the rope. (For those who don't know how that story ended, the answer is Not Well: the stock that occasioned all this hyperventilation ended up dropping by a factor of nearly a hundred over the next couple of years. The press-released clinical candidate was never, ever, heard of again).

I bring this up because a reader in the industry forwarded me this column from Bio-IT World, entitled, yes, "Only Moore's Law Can Save Big Pharma". I've read it three times now, and I still have only the vaguest idea of what it's talking about. Let's see if any of you can do better.

The author starts off by talking about the pressures that the drug industry is under, and I have no problem with him there. That is, until he gets to the scientific pressures, which he sketches out thusly:

Scientifically, the classic drug discovery paradigm has reached the end of its long road. Penicillin, stumbled on by accident, was a bona fide magic bullet. The industry has since been organized to conduct programs of discovery, not design. The most that can be said for modern pharmaceutical research, with its hundreds of thousands of candidate molecules being shoveled through high-throughput screening, is that it is an organized accident. This approach is perhaps best characterized by the Chief Scientific Officer of a prominent biotech company who recently said, "Drug discovery is all about passion and faith. It has nothing to do with analytics."

The problem with faith-based drug discovery is that the low hanging fruit has already been plucked, driving would be discoverers further afield. Searching for the next miracle drug in some witch doctor's jungle brew is not science. It's desperation.

The only way to escape this downward spiral is new science. Fortunately, the fuzzy outlines of a revolution are just emerging. For lack of a better word, call it Digital Chemistry.

And when the man says "fuzzy outline", well, you'd better take him at his word. What, I know you're all asking, is this Digital Chemistry stuff? Here, wade into this:

Tomorrow's drug companies will build rationally engineered multi-component molecular machines, not small molecule drugs isolated from tree bark or bread mold. These molecular machines will be assembled from discrete interchangeable modules designed using hierarchical simulation tools that resemble the tool chains used to build complex integrated circuits from simple nanoscale components. Guess-and-check wet chemistry can't scale. Hit or miss discovery lacks cross-product synergy. Digital Chemistry will change that.

Honestly, if I start talking like this, I hope that onlookers will forgo taking notes and catch on quickly enough to call the ambulance. I know that I'm quoting too much, but I have to tell you more about how all this is going to work:

But modeling protein-protein interaction is computationally intractable, you say? True. But the kinetic behavior of the component molecules that will one day constitute the expanding design library for Digital Chemistry will be synthetically constrained. This will allow engineers to deliver ever more complex functional behavior as the drugs and the tools used to design them co-evolve. How will drugs of the future function? Intracellular microtherapeutic action will be triggered if and only if precisely targeted DNA or RNA pathologies are detected within individual sick cells. Normal cells will be unaffected. Corrective action shutting down only malfunctioning cells will have the potential of delivering 99% cure rates. Some therapies will be broad based and others will be personalized, programmed using DNA from the patient's own tumor that has been extracted, sequenced, and used to configure "target codes" that can be custom loaded into the detection module of these molecular machines.

Look, I know where this is coming from. And I freely admit that I hope that, eventually, a really detailed molecular-level knowledge of disease pathology, coupled with a really robust nanotechnology, will allow us to treat disease in ways that we can't even approach now. Speed the day! But the day is not sped by acting as if this is the short-term solution for the ills of the drug industry, or by talking as if we already have any idea at all about how to go about these things. We don't.

And what does that paragraph up there mean? "The kinetic behavior. . .will be synthetically constrained"? Honestly, I should be qualified to make sense of that, but I can't. And how do we go from protein-protein interactions at the beginning of all that to DNA and RNA pathologies at the end, anyway? If all the genomics business has taught us anything, it's that these are two very, very different worlds - both important, but separated by a rather wide zone of very lightly-filled-in knowledge.

Let's take this step by step; there's no other way. In the future, according to this piece, we will detect pathologies by detecting cell-by-cell variations in DNA and/or RNA. How will we do that? At present, you have to rip open cells and kill them to sequence their nucleic acids, and the sensitivities are not good enough to do it one cell at a time. So we're going to find some way to do that in a specific non-lethal way, either from the outside of the cells (by a technology that we cannot even yet envision) or by getting inside them (by a technology that we cannot even envision) and reading off their sequences in situ (by a technology that we cannot even envision). Moreover, we're going to do that not only with the permanent DNA, but with the various transiently expressed RNA species, which are localized to all sort of different cell compartments, present in minute amounts and often for short periods of time, and handled in ways that we're only beginning to grasp and for purposes that are not at all yet clear. Right.

Then. . .then we're going to take "corrective action". By this I presume that we're either going to selectively kill those cells or alter them through gene therapy. I should note that gene therapy, though incredibly promising as ever, is something that so far we have been unable, in most cases, to get to work. Never mind. We're going to do this cell by cell, selectively picking out just the ones we want out of the trillions of possibilities in the living organism, using technologies that, I cannot emphasize enough, we do not yet have. We do not yet know how to find most individual cells types in a complex living tissue; huge arguments ensue about whether certain rare types (such as stem cells) are present at all. We cannot find and pick out, for example, every precancerous cell in a given volume of tissue, not even by slicing pieces out of it, taking it out into the lab, and using all the modern techniques of instrumental analysis and molecular biology.

What will we use to do any of this inside the living organism? What will such things be made of? How will you dose them, whatever they are? Will they be taken up though the gut? Doesn't seem likely, given the size and complexity we're talking about. So, intravenous then, fine - how will they distribute through the body? Everything spreads out a bit differently, you know. How do you keep them from sticking to all kinds of proteins and surfaces that you're not interested in? How long will they last in vivo? How will you keep them from being cleared out by the liver, or from setting off a potentially deadly immune response? All of these could vary from patient to patient, just to make things more interesting. How will we get any of these things into cells, when we only roughly understand the dozens of different transport mechanisms involved? And how will we keep the cells from pumping them right back out? They do that, you know. And when it's time to kill the cells, how do you make absolutely sure that you're only killing the ones you want? And when it's time to do the gene therapy, what's the energy source for all the chemistry involved, as we cut out some sequences and splice in the others? Are we absolutely sure that we're only doing that in just the right places in just the right cells, or will we (disastrously) be sticking in copies into the DNA of a quarter of a per cent of all the others?

And what does all this nucleic acid focus have to do with protein expression and processing? You can't fix a lot of things at the DNA level. Misfolding, misglycosylation, defects in transport and removal - a lot of this stuff is post-genomic. Are we going to be able to sequence proteins in vivo, cell by cell, as well? Detect tertiary structure problems? How? And fix them, how?

Alright, you get the idea. The thing is, and this may be surprising considering those last few paragraphs, that I don't consider all of this to be intrinsically impossible. Many people who beat up on nanotechnology would disagree, but I think that some of these things are, at least in broad hazy theory, possibly doable. But they will require technologies that we are nowhere close to owning. Babbling, as the Bio-IT World piece does, about "detection modules" and "target codes" and "corrective action" is absolutely no help at all. Every one of those phrases unpacks into a gigantic tangle of incredibly complex details and total unknowns. I'm not ready to rule some of this stuff out. But I'm not ready to rule it in just by waving my hands.

Time for a quick blogroll update. Heading into the various science and pharma blog category over on the left are PK/PD, BBSRC/Douglas Kell, and Sigma-Aldrich ChemBlogs. Enjoy!

I wrote last summer about Vanda Pharmaceuticals and their difficulty getting a new antipsychotic Fanapt (iloperidone) through the FDA. At the time, they'd received one of those wonderful requests for more information from the agency, of the kind that spread cheer whenever they appear. I couldn't see how the company could clear this up without (probably) having to spend a lot of money that it didn't have, and I was very pessimistic about their survival.

And I was wrong. Big-time. Vanda received approval for iloperidone, in what is a major surprise not just for me, but for the company's hardy shareholders and for the few analysts left covering them. After congratulating the company, I feel like asking them "So, how did you do that, anyway?" To the best of my knowledge, the company didn't go back into the clinic - and it's hard to see how they even could have. Less than a year just isn't feasible from a standing start in an antipsychotic trial just on logistic grounds, let alone the fact that Vanda doesn't seem to have had the funds to even try.

So was this all just a regrettable misunderstanding? And if so, on whose part? Did the FDA misinterpret something, only to be argued back by the company? Or did Vanda mess something up in the original regulatory package? We may never know.

The question now that the dog has caught the mail truck is what to do with it. No deal has been announced yet to market the compound, and Vanda still doesn't seem to have the funds to sell it by itself. (Moreover, they don't seem to be recruiting a sales force). Some observers think that the company may have had time selling itself off, and that the run in the stock was overdone just for that reason.

In the meantime, though, the company should enjoy its good fortune (as should anyone who was holding its stock when the news hit). And readers of this blog should make a note that, in case there was any doubt, I can be completely, totally wrong about the field I work in. . .

Sanofi is saying "no layoffs" in their announcement today, but is instead counting on "voluntary staff departures". Here's the press release, courtesy of Fierce Biotech, notable for its relentless insistence on not capitalizing the name of the company.

I'm not sure how those voluntary departures are supposed to work - I can tell you it would take a lot to get anyone in R&D to volunteer to leave their job in this climate. So, generous - very generous - buyouts are one way, and sheer attrition is another (although turnover must not be so high these days either, with fewer places to go). The press release is rather short on details. Don't believe me? Chew on this:

"To implement this new R&D model, sanofi-aventis will group researchers in more productive structures and engage in recruiting and training to adapt the profiles and skills of its collaborators to the demands of these mutations. The model also includes strengthening 'exploratory structures' that work in close collaboration with outside entities and deploying reactive 'entrepreneurial units' to encourage the emergence of innovation and accelerate the marketing of innovative products."

Well, OK, then! I guess we'll have to wait some more for this fog to condense into something recognizable.

Organic synthesis as we know it can't go on without metal-catalyzed bond-forming reactions. There are too many of them, and they're just too useful. Palladium's the workhorse, followed by copper, then you've got rhodium, nickel, and a host of others (gold's been popular the last few years). We have a. . .fairly good idea of what's going on in these reactions, but not quite good enough. If we really understood all the factors involved, there wouldn't be six garbonzillion different sets of conditions for these things, would there?

A short paper's just come out in Angewandte Chemie that illustrates some of the trickiness involved. Carsten Bolm's group at Aachen has published several interesting iron-catalyzed coupling reactions using good old ferric chloride. These are aryl-amine, aryl-ether, aryl-amide and aryl-sulfide-forming procedures, which cover a lot of ground. (Interestingly, it was one of those sulfide papers that was recently plagiarized by another set of authors). But there were always a few kinks, such as variable yield depending on which bottle of ferric chloride was used.

Well, organometallic chemists are used to that sort of thing. But Bolm has gone back to look at things closely, in collaboration with Stephen Buchwald of MIT (whose group has published many similar couplings with other metal systems), and found a surprise. The iron chloride isn't doing a thing. In fact, as you go to more and more pure sources of the reagent, the yield drops off. But it never goes away, even with the 99.9% pure stuff. That's because it seems to be copper (I) contaminants doing the coupling, even at the parts-per-million level.

There are some startling tables in the paper. For coupling pyrazole onto an aryl iodide, for example, Bolm's group had found in 2007 that they could get 87% yield using >98% ferric chloride from E. Merck, along with dimethylethylene diamine as a cosolvent. If you use the >98% from Aldrich under the same conditions, though, you get 26% yield. And the Aldrich >99.99 stuff gives you only 9%. But if you add five ppm copper (I) oxide to that last reaction, the yield goes up to 78%. And if you leave the ferric chloride out completely, and just go with a trace of copper, the yield is exactly the same (it goes down if you run the same trace-of-copper without the diamine, which seems to be complexing it up into solution).

The other couplings that were reported seem to follow the same pattern. This must really be a disappointment to Bolm and his group, because their work was, among other things, an attempt to get away from copper and palladium. Still, this appears to be a much cleaner and more efficient copper reaction than a lot of the procedures out there.

This sort of thing has happened before in organometallic chemistry. There's a well-known example of nickel contamination in a chromium-mediated reaction from the mid-1980s, and more recently, a report of supposed "metal-free" couplings which appear to have been catalyzed by parts-per-billion levels of palladium found in the sodium carbonate being used as a base, of all things. Tricky things, these metals.

Not long ago, I wrote about a Pfizer program for smaller companies to come screen their targets against Pfizer's compound bank. Now Eli Lilly has flipped that around. In an initiative to bring other people's compounds out of the stockrooms and off the shelves, they'll screen them for free.

These aren't single-target assays. The company has four phenotypic screens going (for Alzheimer's, diabetes, cancer, and osteoporosis) and will look for improvement by any mechanism that comes to hand. No chemical structure information is shown to Lilly (I assume that they just know the molecular weight so they can run a dilution series). If something looks interesting, the company and the owners of the chemical matter have 120 days to come to terms for any further development deal - if not, then all rights revert to the submitter, and they can publish the data from the screens.

Lilly's working out a universal material transfer agreement, in collaboration with a number of universities, so that the paperwork stays the same every time. That's a good move. The lawyering can be a real holdup - in my experience, every party in these agreements usually comes in with slightly different wording in their magic legal spells, requiring several rounds of reconciliation before everyone's ready to sign.

I think that this is a worthwhile idea, and that they'll get a lot of takers. There are plenty of compounds sitting around in academic labs gathering dust, so why not send 'em in? The worst that can happen is nothing, and the best is that the compound actually turns out to be worth something. But will anything come out of it? The closest program to this is surely the National Cancer Institute's long-standing (since 1990) NCI-60 screening program, which also runs at no cost to the submitters. Even so, a recent reference mentions that there are between 40,000 and 50,000 compound in the NCI database, which actually seems rather small, considering. (To be fair, the program is not being funded at the levels that it was during the early 1990s). The only marketed compound that I'm aware of that can be said to have come out of the NCI-60 screen is Velcade (bortezomib), known then as PS-341, which was sent in for screening by Proscript Pharmaceuticals in the mid-1990s. Many other interesting structures have turned up along the way, though, which for various reasons haven't made it all the way through.

It'll be quite interesting to see what sort of hit rate Lilly's phenotypic assays call up - I hope they tell us. I have a lot of sympathy for the mechanism-agnostic approach myself, and I'd like to see how closely my bias are aligned to reality.

I missed commenting on this earlier, but many readers may have noticed the recent scandal caused by Zicam. This is a cold remedy which was sold as a homeopathic medicine, but its makers committed the unforgivable sin of actually having something in its formula besides well-shaken distilled water.

A lot of people are convinced that zinc is good for colds - I'm agnostic, having not seen much convincing evidence - so if that's the case, why not snort zinc up your nose? That, at any rate, seems to be the condensed version of the Zicam pitch, although I don't believe that they used that exact wording in their ads. (A gift for advertising copy might not be one of my more robust talents. . .) At any rate, snorting zinc salts has actually been known, for some time now, to injure the sense of smell in some people. So it's proved with Zicam, with several hundred victims.

The moral? If you're going to sell homeopathic medicine - and boy, is it a lucrative business - make sure that you don't put anything in there except sterile water. That'll cut down on your expenses, too, since most ingredients cost more than water, anyway. Stick with that strategy, and you can be absolutely sure that nothing bad will happen to your customers. Nothing good will happen to them either, but they won't know that. When their cold/headache/whatever goes away of its own accord, they'll ascribe it to your miracle product. Sit back and profit! Be sure to thank Senator Hatch while you count your money, though - it's only proper.

Via a reader comes this article, which takes us to Elsevier's hard-hitting textbook publishing operation. The co-authors of a psychology text for the publisher were recently taken aback to get this e-mail from a publicist at the company:

""Congratulations and thank you for your contribution to Clinical Psychology. Now that the book is published, we need your help to get some 5 star reviews posted to both Amazon and Barnes & Noble to help support and promote it. As you know, these online reviews are extremely persuasive when customers are considering a purchase. For your time, we would like to compensate you with a copy of the book under review as well as a $25 Amazon gift card. If you have colleagues or students who would be willing to post positive reviews, please feel free to forward this e-mail to them to participate. We share the common goal of wanting Clinical Psychology to sell and succeed. The tactics defined above have proven to dramatically increase exposure and boost sales. I hope we can work together to make a strong and profitable impact through our online bookselling channels."

George Tremblay of Antioch U. blew the whistle on this one, which is a good deed. But, cynical person that I am, it makes me wonder how many others on the list might have been ready to pitch in. And given that this has apparently been done before (hey, this is a "proven" strategy), you also have to wonder about five-star reviews of other textbooks published by Elsevier. And other houses, too?

I ask because the company's director of public relations has come out to explain just where this latest tactic went too far - and I have to say, it's a bit further along the line than many people might have thought:

"Encouraging interested parties to post book reviews isn't outside the norm in scholarly publishing, nor is it wrong to offer to nominally compensate people for their time, some of these books are quite large," he said. "But in all instances the request should be unbiased, with no incentives for a positive review, and that's where this particular e-mail went too far."

So when you're encouraging people to write reviews, and offering them some baksheesh for doing so, that's fine. You just don't want to be so gauche as to actually come out and say that you want the reviews to be positive. This does not make Elsevier look good, of course, coming as it does after the reheated-tray-of-friendly-leftovers journal scandal in Australia. (And let's not forget the, um, unusual case of El Naschie and his private Elsevier journal of nonsense). They either are the poor victims of widely scattered unethical promotions staff, or (just perhaps) there's a general culture in that department that allows people to think that these things are acceptable practice.

There's a lot of talk that something big is going to happen at Sanofi-Aventis next week. What we don't know is whether this is a sales-and-marketing change, a mostly-European change, or what. The company's been through layoffs already, but hey, in this climate, who hasn't? More on this as something reliable emerges. . .

There are some interesting statements from GlaxoSmithKline CEO Andrew Witty here at Reuters. He admits that morale was completely in the scupper around the place a few months ago, which certainly seems to be true, but says that they're turning things around. To that point, remember all that stuff a few years ago about how GSK's research structure exemplified pretty much everything that a drug company needed to have? Well. . .

"We've really thrown into reverse much of the trend of research organisation that had developed over the last 15 years," Witty said.

Over that time, the drugs industry was a big commercial success but it took a "wrong turn" by deciding that drug discovery was an industrial process based on large-scale application of technologies like genomics, proteomics and combinatorial chemistry.

"These were all supposed to transform productivity yet none of them did. It turns out, in my view, that research is much more of an art than a science," Witty said.

Several thoughts come to mind. First off, I take the point about art versus science, but it's hard to do art on an industrial scale. That, to my mind, has been one of the major problems in all of drug R&D. He's right that the industry keeps seizing on things that promise to take some of the craziness out of the process - but it's not like the temptation isn't still around. We just haven't seen the latest brainwave yet.

But still, over time, some of the random element has decreased. We actually do understand a lot of things better than we used to. We know to look for hERG, to pick one example, and there are others. But these things don't (yet) add to enough of a transformation. Adding more and more knowledge to the pile has to help - I'm certainly not enough of a nihilist to deny that - but it's fair to say that it hasn't helped as quickly and as thoroughly as we might have hoped.

You can find opinions all up and down that spectrum: at one end are the nihilists themselves, who hold that the problems we're trying to solve are (at present) too hard, and what's more, they're likely to remain too hard for the foreseeable future, so you'd better get lucky - and design your research structure to improve your chances of doing that. Moving up from there, you have a lot of people in the middle who see incremental progress, but (with Goethe) worry that "Where there is much light, there is much darkness". Every new advance untangles a few things, but also ends up illustrating how much more we need to know. Opinions in this crowd vary, from pessimists who come close to the first nihilist group, all the way up to optimists who hold out hope that things will start making more sense soon. And past them, you come to the super-optimists, the Kurzweilians who are waiting for the Singularity.

But finally, reading the Witty article, I can't help but imagine an interview in around 2020, with whoever's in charge then talking about how they had to get rid of all that musty old research structure that the previous management team had put in. . .

I appreciate the mail I've had on this subject, and wanted to provide a brief update for those who are interested. If you've set up a proxy server for Iran, you can submit it here - Austin Heap is the guy running this part of the effort. There's also a test page where you can see if you have things configured correctly. Anyone needing more technical details, please drop me a note - I'll either answer it myself or send you on to someone who can. I am, truth be told, not exactly one of the 1337-est haxors around, but one does what one can.

What's really going on with Medarex and ipilimumab? The company made news over the weekend with a press release from the Mayo Clinic, detailed what appears to be a substantial response in two prostate cancer patients. But the more you look at the story, the harder it is to figure out anything useful.

As this WebMD piece makes clear, this study is not a trial of ipilimumab as a single agent. The patients are undergoing prolonged androgen ablation, the testosterone-suppressing therapy that's been around for many years and is one of the standard options for prostate cancer. The trial is to see if ipilimumab has any benefit when it's added to this protocol - basically, to see if it can advance the standard of care a bit.

WebMD quotes Derek Raghavan at the Cleveland Clinic as saying that androgen ablation can sometimes have dramatic results in patients with locally advanced prostate cancer, so it's impossible to say if ipilimumab is helping or not. That's why we run clinical trials, you know, to see if there's a real effect across a meaningful number of patients. But (as this AP story notes) we don't know how many patients are in this particular study, what its endpoints are, or really anything about its design. All we know is that two patients opted out of it for surgery instead. (Credit goes to the AP's Linda Johnson for laying all this out).

Ipilimumab is an antibody against CTLA-4, which is an inhibitory regulator of lymphocytes. Blocking it should, in theory, turn these cells loose to engage tumor cells more robustly. (It also turns them loose to engage normal tissue more robustly, too - most of the side effects seem to be autoimmune responses like colitis, which can be very severe. The antibody has been studied most thoroughly in melanoma, where it does seem to be of value, although the side effect profile is certainly complicating things.

So overall, I think it's way too early to conclude that Medarex has hit on some miracle prostate cure. This press release, in fact, hasn't been too helpful at all, and the Mayo people really should know better.

The In Vivo Blog has a piece that everyone who follows small-company press releases should read. "When Is a Billion Dollars Not a Billion Dollars?", they ask. And the answer is, of course, when someone's press-releasing it. Read the whole thing, but here's the short form: when someone says "We just signed a deal worth a billion dollars!", too often they're leaving out the rest of the sentence. It's supposed to continue like this: ". . .if every single thing goes perfectly and all our drugs work and become the biggest successes they possibly can." And since that happens, like, all the flippin' time, well. . .

Earlier this month I posted about rolofylline, which I noted has a rather unusual noradamantane attached to it. Now check out this ORL-1 compound from Banyu, complete with the not-so-widely-heard-of bicycloheptane-spirocyclopropane group.

This was not arrived at lightly, as you'd imagine. There's a table in the Supporting information for the paper, but I'll quote from the body of the main manuscript:

Various kinds of cycloalkanes, substituted or nonsubstituted cyclopropyl rings to medium sized rings (such as cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl), spiroalkane (such as spiro[2.5]octanemethyl, spiro[3.5]nonanemethyl, spiro[4.5]decanemethyl, spiro[2.4]heptanemethyl, spiro[3.4]octanemethyl, spiro[4.4]nonanemethyl), bicycloheptane (such as methylbicyclo[2.2.1]heptylmethyl, dimethylbicyclo[2.2.1]heptylmethyl, spirocyclopropanebicycloheptanemethyl), and branched alkanes (such as 3,3-dimethylbutane, 3,3-dithylbutane, 1-methylcyclobutaneethyl, 1-methylcyclopentaneethyl, 1-methylcyclohexaneethyl) were tested.

No, that couldn't have been a lot of fun. Anyone else out there found themselves having to optimize grease recently?

We organic chemists have it easy compared to the cell culture people. After all, our reactions aren't alive. If we cool them down, they slow down, and if we heat them up, they'll often pick up where they left off. They don't grow, they don't get infected, and they don't have to be fed.

Cells, though, are a major pain. You can't turn your back on 'em. Part of the problem is that there are, as yet, no cells that have evolved to grow in a dish or a culture bottle. Everything we do to them is artificial, and a lot of it what we ask cultured cells to do is clearly not playing to their strengths. Ask Genzyme: they use the workhorse CHO (Chinese Hamster Ovary) cells to produce their biologics, but they've been having variable yield problems over the past few months. Now it turns out that their production facilities are infected with Vesivirus 2117 - I'd never heard of that one, but it interferes with CHO growth, and that's bringing Genzyme's workflow to a halt. (No one's ever reported human infection with that one, just to make that clear).

I assume that the next step is a complete, painstaking cleanup and decontamination. That's going to affect supplies of Cerezyme (imiglucarase) and Frabazyme (agalsidase) late in the summer and into the fall, although it's not clear yet how long the outage will be. Any cell culture lab that's had to toss things due to mycoplasms or other nasties will sympathize, and shudder at the thought of cleaning things up on this scale.

Anyone who needs pointers on setting up an Iran proxy server, drop me an e-mail; I'll send over the information. There are quite a few technical updates, but I'll only inflict them on those who need 'em. And as for this news story, the Boston Globe reporter asked me "Hey, you're that In the Pipeline guy", aren't you?"

After yesterday's post on pathway patents, I figured that I should talk about high-throughput screening in academia. I realize that there are some serious endeavors going on, some of them staffed by ex-industry people. So I don't mean to come across as thinking that academic screening is useless, because it certainly isn't.

What is probably is useless for is enabling a hugely broad patent application like the one Ariad licensed. But the problem with screening for such cases isn't that the effort would come from academic researchers, because industry couldn't do it, either: Merck, Pfizer, GSK and Novartis working together probably couldn't have sufficiently enabled that Ariad patent; it's a monster.

It's true that the compound collections available to all but the very largest academic efforts don't compare in size to what's out there in the drug companies. My point yesterday was that since we can screen those big collections and still come up empty against unusual new targets (again and again), that smaller compound sets are probably at even more of a disadvantage. Chemical space is very, very large. The total number of tractable compounds ever made (so far) is still not a sufficiently large screening collection for some targets. That's been an unpleasant lesson to learn, but I think that it's the truth.

That said, I'm going to start sounding like the pointy-haired boss from Dilbert and say "Screen smarter, not harder". I think that fragment-based approaches are one example of this. Much smaller collections can yield real starting points if you look at the hits in terms of ligand efficiency and let them lead you into new chemical spaces. I think that this is a better use of time, in many cases, than the diversity-oriented synthesis approach, which (as I understand it) tries to fill in those new spaces first and screen second. I don't mind some of the DOS work, because some of it's interesting chemistry, and hey, new molecules are new molecules. But we could all make new molecules for the rest of our lives and still not color in much of the map. Screening collections should be made interesting and diverse, but you have to do a cost/benefit analysis of your approach to that.

I'm more than willing to be proven wrong about this, but I keep thinking that brute force is not going to be the answer to getting hits against the kinds of targets that we're having to think about these days - enzyme classes that haven't yielded anything yet, protein-protein interactions, protein-nucleic acid interactions, and other squirrely stuff. If the modelers can help with these things, then great (although as I understand it, they generally can have a rough time with the DNA and RNA targets). If the solution is to work up from fragments, cranking out the X-ray and NMR structural data as the molecules get larger, then that's fine, too. And if it means that chemists just need to turn around and generate fast targeted libraries around the few real hits that emerge, a more selective use of brute force, then I have no problem with that, either. We're going to need all the help we can get.

Nature Biotechnology has a good wrap-up of the Ariad patent case, and it includes some insights into the whole "patent the pathway and profit" mindset. That was the heart of Ariad's strategy: they licensed a patent on NF-kappaB from Harvard, MIT, and the Whitehead institute, and promptly went wild threatening to sue everyone that came within a mile of its already ridiculously vast) claims.

I particularly like this description of the legal process involved:

. . .Despite the earlier jury verdict in Ariad's favor, "the federal circuit [court] treated these claims, you know, almost derisively. They just smacked them," says Minnesota patent attorney Warren Woessner, former chair of the biotech committee of the American Intellectual Property Law Association. Woessner had predicted Ariad's defeat. "They won in a jury trial—big deal. They got some Nobel prizewinners up there to say how wonderful this was, and the jury folded like a cheap lawn chair. That's not uncommon. But the [appeals judges] just demolished this."

Indeed. But the strategy isn't dead yet, unfortunately:

Companies asserting broad claims "are not going to get much sympathy" from the federal circuit, agrees (Duke's Arti) Rai. "And if they're trying to assert them against a defendant who is as willing to fight as Eli Lilly is, they're ultimately going to lose."

Many universities, however, emboldened by Ariad's 2006 district court victory, have been pressing for such broad claims. "Every professor that discovers a mechanism of action now wants you to claim it," says Woessner, who advises universities. "And it can be hard to dissuade them from that." The take-home lesson from the Ariad case, says Woessner, is that filing such broad claims, without specifying compounds, hoping that some will stand, is a risky patent strategy. "Don't try to get broad functional claims, like the Ariad claims, or the Rochester claims," he says, without describing specific pathway modulators.

Ah, but coming up with specific pathway modulators is often the job of. . .(drumroll) a drug company. One that's full of medicinal chemists who know how to try to optimize these things. Unless an academic group gets lucky in screening a smaller commercial compound collection, they're not likely to be able to show such enabling compounds. And since most academic researchers don't have access to anything like the industry's high-throughput screening technology, let alone the industry's files of plausible-looking molecules, the chances aren't good. Heck, they aren't all that good for us over here, and we have all those things. To get the full flavor, you really need to see some big HTS campaigns rummage expensively through a whopping compound collection and still come up with only 3-hydroxy-diddleysquat. . .

Just a quick update to my post the other day on proxies for the Iranian protestors. The San Francisco Chronicle has an article on Austin Heap, the fellow whose web site I linked to the other day. He and a number of collaborators are doing a lot of hard work trying to keep lines of communication open from inside Iran.

If any of you are trying the proxy server thing (as I am with my home machine), be sure to check this update. You'll need to make some adjustments, since the (current!) Iranian government isn't making this easy, naturally.

There are other information tunnels, which rapidly get to be beyond my own hardware resources and hacking skills, but many people seem to be at work on these. One interesting addition to the fray is the anti-Scientology group known as Anonymous. Since my opinion of Scientology is nearly as low as my opinion of the Iranian government, I can only welcome this meeting of the minds.

There's a good article from Lee Howard up at The Day (the New London/Groton newspaper) on the changes going on at Pfizer. It's the story according to management, though, which is worth having for its compare-and-contrast uses:

Despite the looming uncertainty, according to company spokesmen, the new research structure has added energy and urgency to the drug-discovery process in Groton. . .

. . .The changes in Groton - seen most plainly in displays of logos the new business units are in the process of choosing - have added drug-development staff and even legal experts to the R&D mix, along with biologists and chemists who typically have worked in close proximity. In the middle of it all sits the chief scientific officer of each business unit, as well as other managers.

The idea is to develop a more realistic idea of a drug's likelihood to succeed at an early stage and then bring it to market quicker if it seems to be working.

I hope that the process of choosing new logos doesn't take too long. You could get a reasonable read on the success of any attempt to remake Pfizer's culture by counting the number of meetings the logo process has required so far.

But I can't make fun of the goals that the company is setting - they're perfectly sensible. The only problem is that they're just what everyone else is trying to do, too, and if it were easy, everyone would be finished doing them by now. The problem with trying to get an earlier decision of a drug's chances for success are that many of the serious problems don't show up (in fact, can't show up) until larger clinical trials. And I don't think that anyone's got a good way around that one yet. Some therapeutic areas are better suited than others, to be sure.

Would the new structures that Pfizer's putting in place have prevented the torcetrapib disaster? I doubt it - that one took everyone by surprise. Would they have prevented the Exubera disaster? Now, that one's food for thought, because it seemed to be much more self-inflicted. If the company can avoid doing that sort of thing again, then they've accomplished something.

And for all the nasty things I say about Pfizer here, I hope that they do accomplish things. After all, they're the biggest drug company in the world, and they seem determined to stay that way. If an organization that huge ends up spinning its wheels (or sitting around designing new business cards), it can't be good for anyone.

Many thanks to the people who've e-mailed me about the situation in Iran. My wife's relatives there are all OK (so far!); she's spoken to them several times. Things remain unstable and impossible to predict. It's been thirty years since huge crowds marched through the streets shouting "Death to the Dictator", so everyone's a bit out of practice.

One thing that the more technically inclined readers might consider doing is setting up proxy servers for use by the Iranian protesters. Two web sites that will give you details on this are here and here. The government is blocking all the obvious IP addresses for people trying to organize and get news out of the country, but anonymous proxies provide a lot of non-obvious routes onto the net. I'm trying to get something set up at home myself.

There are a lot of punches being thrown by both sides - for example, some people with proxy servers have reported a lot of denial-of-service garbage coming in from blocks of Russian and Chinese IP addresses. But if you configure things to accept only Iranian domains (those sites above have IP address lists) you should be able to screen that stuff. If you're up for it, please consider helping out. It's one of the few concrete steps I can think of from this distance. A general guide to the current cyberwarfare situation is here. Update - link went dead, but this new one will stay alive. BoingBoing has enough bandwidth!

Yesterday's post on so-called "ugly" molecules seems to have touched a few nerves. Perhaps I should explain my terms, since ugliness is surely in the eye of the beholder. I'm not talking about particular functional groups as much as I'm talking about the whole package.

First off, a molecule that does what it's supposed to do in vivo is (by my definition) not truly ugly. The whole point of our job as medicinal chemists is to make active compounds - preferably with only the activity that we want - and if that's been accomplished there can be no arguing. Of course, "accomplished" has different meanings at different stages of development. Very roughly, the mileposts (for those of us in discovery research) are:

1. Hitting the target in vitro.
2. Showing selectivity in vitro.
3. Showing blood levels in vivo.
4. Showing activity in vivo.
5. No tox liabilities in vivo.

And these all have their gradations. My point is that if you've made it through these, at least to a reasonable extent, your molecule has already distinguished itself from the herd. The problem is that a lot of structures will fly through the first couple of levels (the in vitro ones), but have properties that will make it much harder for them to get the rest of the way. High molecular weight, notable lack of polarity (high logP), and notable lack of solubility are three of the most important warning signs, and those are what (to me) make an ugly molecule, not some particular functional group.

My belief is that, other things being equal, you should guard against making things that have trouble in these areas. You may well find yourself being forced (by the trends of your project) into one or more of them; that happens all the time, unfortunately. But you shouldn't go there if you don't have to. It's also true that there are molecules that have made it all the way through, that are out there on the market and still have these liabilities. But that shouldn't be taken as a sign that you should go the same route.

Ars longa, vita brevis. There's only so much time and so much money for a given project, and your time is best spent working in the space that has the best chance of delivering a drug. A 650 molecular weight compound with five trifluoromethyl groups is not inhabiting that space. It's not impossible that such a compound will make it, but I think we can all agree that its chances are lower compared to something smaller and less greasy. If the only thing you can get to work is a whopper like that, well, good luck to all concerned. But we have to depend on luck too much already in this business, and there's no reason to bring in more.

I've been involved in another outbreak of the perennial debate about what kinds of compounds medicinal chemists should be making. I can summarize the way this usually goes:

Chemist A: "Look at all these ugly molecules! Why can't we institute some sort of "No-Suzuki-Coupling" rule for two days out of every week or something? Failing that, why doesn't everyone at least try to make things that look better from the start?"

Chemist B: "Nice thought - but the most potent molecules tend to be on the uglier end of the spectrum. And once you've made a single-digit nanomolar compound for the first time in a new project, it's impossible to walk away from it. It's almost like you get to choose: good physical properties, or good activity and selectivity."

Chemist A: "Don't look in these places if you don't want to find what's there. I'm tired of people making big insoluble monster compounds "just for SAR purposes". Because then some of them hit, and you're stuck with 'em."

Chemist B: "But I can't go give a project update and say that we found the most potent compound ever, but we're not going to follow up on it. And then spend the rest of the time telling everyone that we made a whole bunch of compounds with great properties, but hey, they have no activity. That's not going to do me (or anyone else) any good, right?"

Chemist A: "That's why you don't make the uglies in the first place, so you don't get put in that bind. Of course, what everyone says to do is to take that potent ugly compound and make it better, now that you've found it. Problem is, most of the time the things you do to make it "better" start to kill the activity. We'd be better off with fewer hot compounds, as long as the ones we had were decent."

And so it goes. This same debate has gone on in my other workplaces, too, and I believe that it's a general one across the industrial labs. Who's winning the argument at your shop?

My Twitter account usually only gets my posts on this blog (the first 140 characters of them, that is). But those of you who follow me there have been flooded with updates of a very different kind for the last 24 hours or so. My Iranian-born wife and I have been watching the news carefully, as the Iranian election situation seems to be getting out of control. She's been translating Farsi-language updates, and I've been reposting them - there will probably be more of this over the next few days.

You can imagine where my sympathies lie, as a non-religious guy with libertarian leanings. Confusion and bad luck to the mullahs, to everyone who helped them steal this election, and to their henchmen beating members of the opposition in the streets. Freedom of speech, freedom of assembly, and freedom of electoral choice are easy to take for granted in some parts of the world, but none of them come easy.

And more to the usual subject of this blog: the Iranians have produced a lot of top-notch people in science, medicine, and engineering - I've seen and worked with many of them. But I'd love to be able to see what they could accomplish working from a free and stable country, and I hope I get the chance. We'll see.

If you're looking for news, #iranelection on Twitter is a firehouse of information, good and bad, and will lead you to plenty of other sites. The National Iranian American Council is an excellent source, and Andrew Sullivan is doing a fine job covering the situation, too.

Well, this doesn't look good for Lilly. A huge pile of court documents has been unsealed in the ongoing lawsuits about Zyprexa's off-label promotion. The company has already paid some serious fines, and is now fighting it out with insurance companies and other plaintiffs who are seeking to recover their costs. Several states are suing them as well; those cases are still on their way.

Bloomberg News was given a lengthy list of internal company statements that will surely be difficult to explain in court. These were provided by one of the plaintiff's attorneys, Hagens Berman Sobol Shapiro LLP, so it's hardly a neutral selection (as Lilly is saying in response). But it's going to be interesting to see what sorts of explanations the company has for these. On the one hand, you have this:

In 1998, Lilly went back to the FDA seeking approval to market Zyprexa to those battling Alzheimer’s, the most common form of dementia, the company said in its 2003 request for a meeting on a proposed label change. Lilly withdrew its bid to promote Zyprexa for Alzheimer’s cases in 1999, according to the document.

In a November 2000 memo to Lilly salespeople, company executives said the dementia marketing initiative was abandoned because the FDA questioned Zyprexa’s effectiveness in treating the ailment.

“It was withdrawn due to vagueness on the FDA’s part regarding a definition of efficacy,” Lilly officials said in the document.

In a 2003 memo to FDA regulators citing the clinical studies, Lilly researchers acknowledged the death rates among older dementia patients on Zyprexa in the reviews were two times higher than their counterparts taking placebos.

Deaths among the patients taking Zyprexa in the studies were “significantly greater than placebo-treated patients (3.5 percent v. 1.5 percent, respectively),” Lilly officials said, according to the unsealed documents.

The studies didn’t find Zyprexa was effective in treating dementia, the company acknowledged in this document.

Lilly recognized this earlier, according to a 2002 document entitled “Zyprexa in serious mental illness (65 plus years) -- A Strategy Review.”

“The treatment of serious mental illness for people over the age of 65 has been identified as a growing opportunity for Zyprexa,” the authors wrote. “Unfortunately, attempts to gain the data to support an application for an indication in the treatment of dementia have to date been unsuccessful.”

But on the other hand, we have:

Lilly’s long-term care unit also saw Zyprexa sales rise 2.9 percent in the second quarter of 2002 as sales of Risperdal, Johnson & Johnson’s rival antipsychotic, fell, according to the 2002 marketing plan.

At that time, long-term care sales made up about 20 percent of Zyprexa prescriptions, according to the summary. Of that number, 65 percent were written for nursing-home patients.

Overall, prescriptions for older patients were the “2nd biggest money-producing segment” for Zyprexa in the U.S., according to a Feb. 15, 2002, e-mail from Lilly researcher Peter Feldman to Denice Torres, the company’s global marketing director.

In that e-mail, Feldman said company officials were saying in internal memos that they were going to stop studying Zyprexa’s potential health benefits for elderly consumers.

That would risk “killing the goose that lays the golden eggs to save on poultry feed costs,” Feldman said in the unsealed messages.

Torres assured him older consumers would continue to be a prime target for Zyprexa sales, according to the e-mail.

“Elderly remains an important aspect of target PT and affiliate focus,” she said in the message.

Increased Zyprexa sales to elderly patients also won Lilly’s long-term care unit praise in a 2003 newsletter unsealed as part of the documents.

“For two consecutive years, you have been on top and have turned in above-plan performance,” Grady Grant, Lilly’s national sales director, wrote in the newsletter. “I look forward to working with you as we set our sights on overtaking Risperdal as the number one antipsychotic in the marketplace!”

Lilly says these are cherry-picked quotes taken out of context. I'll await seeing what context they can be put in that will make them look less like. . .what they look like now.

I spoke here about Scigen, the program that'll concoct a load of total nonsense for you and make it look - from a distance - like a journal paper. It's a surprisingly valuable tool, since the scientific publishing world apparently has a bigger demand for total nonsense than you might think, especially after the checks clear.

The latest example of this comes from The Scholarly Kitchen, where Philip Davis generated "Deconstructing Access Points", a paper that's nothing but a string of gibberish and non sequitars from first to last. It's here (in PDF form) if you want to try reading it. You won't get far; no human could.

Ah, but what if no human bothered to? That's what happened when Davis submitted this compost pile to the Open Information Science Journal, which is one of the new Bentham "open access" journals. You see, Bentham (like some other publishing houses) has heard that this open access stuff is like, the new trend, so they've started a line of their own journals. Once your paper's accepted, anyone can access it. Of course, there is a fee up front - to be fair, there pretty much has to be, if someone is actually going to do the back-end reviewing and editing work of a real journal. But what if you don't do any of that, and just charge the fee anyway?

Yes, the paper was accepted - of course it was accepted. It was accepted despite it being an unreadable mass of pseudo-English, and despite the fact that it was sent in under the banner of the Center for Research in Applied Phrenology. (Nice touch!) Here's the acceptance letter from an assistant manager at Bentham. All Davis had to do was send $800 to a tax-free zone in the United Arab Emirates and this manuscript would be inflicted on the world.

He pulled back at this juncture, but the point had been made. As he puts it, in milder tones than I would have: ". . .it does raise the question of whether, at least in some cases, the producer-pays-to-publish model may unduly influence editorial decision-making." Indeed it does, especially with a lower-tier publisher. Too much of the scholarly publishing world is involved in this sort of thing (and too much of the conference-organizing world, too, for that matter). I know that it's hard for many people to realize this, but it really is better not to publish at all than to abet this sort of thing.

My recent entries in this category have, for the most part, been hazardous in a direct (not to say crude, or even vulgar) manner. These are compounds that explode with bizarre violence even in laughably small amounts, leaving ruined equipment and shattered nerves in their wake. No, I will not work with such.

But today's compound makes no noise and leaves no wreckage. It merely stinks. But it does so relentlessly and unbearably. It makes innocent downwind pedestrians stagger, clutch their stomachs, and flee in terror. It reeks to a degree that makes people suspect evil supernatural forces. It is thioacetone.

Or something close to it, anyway. All we know for sure is that thioacetone doesn't like to exist as a free compound - it's usually tied up in a cyclic thioketal trimer, when it's around at all. Attempts to crack this to thioacetone monomer itself have been made - ah, but that's when people start diving out of windows and vomiting into wastebaskets, so the quality of the data starts to deteriorate. No one's quite sure what the actual odorant is (perhaps the gem-dimercaptan?) And no one seems to have much desire to find out, either.

There are sound historical reasons for this reluctance. The canonical example (Chemische Berichte 1889, 2593) is the early work in the German city of Freiburg in 1889 (see page 4 of this textbook), which quotes the first-hand report. This reaction produced"an offensive smell which spread rapidly over a great area of the town causing fainting, vomiting and a panic evacuation.". An 1890 report from the Whitehall Soap Works in Leeds refers to the odor as "fearful", and if you could smell anything through the ambient conditions in a Leeds soap factory in 1890, it must have been.

The compound shows up sporadically in the literature until the mid-1960s, when several groups looked into thioketones as sources of new polymers. The most in-depth analysis took place at the Esso Research Station in Abingdon, UK, where Victor Burnop and Kenneth Latham got to experience the Freiburg Horror for themselves:

"Recently we found ourselves with an odour problem beyond our worst expectations. During early experiments, a stopper jumped from a bottle of residues, and, although replaced at once, resulted in an immediate complaint of nausea and sickness from colleagues working in a building two hundred yards away. Two of our chemists who had done no more than investigate the cracking of minute amounts of trithioacetone found themselves the object of hostile stares in a restaurant and suffered the humiliation of having a waitress spray the area around them with a deodorant. The odours defied the expected effects of dilution since workers in the laboratory did not find the odours intolerable ... and genuinely denied responsibility since they were working in closed systems. To convince them otherwise, they were dispersed with other observers around the laboratory, at distances up to a quarter of a mile, and one drop of either acetone gem-dithiol or the mother liquors from crude trithioacetone crystallisations were placed on a watch glass in a fume cupboard. The odour was detected downwind in seconds."

Now that's a compound to be taken seriously. How do you work with something that smells like hell's dumpster? Like this:

"The offensive odors released by cracking trithioacetone to prepare linear poly(thioacetone) are confined and eliminated by working in a large glove box with an alkaline permanganate seal, decontaminating all apparatus with alkaline permanganate, eliminating obnoxious vapors with nitrous fumes generated by a few grams of Cu in HNO3, and destroying all residues by running them into the center of a wood fire in a brazier."

So there you have it - just install a fireplace next to your hood (what every lab needs, for sure) and remember that, in a thioacetone situation, fogging the area with brown nitrogen oxide fumes will actually improve the air. (This is from Chemistry and Industry, 1967, p. 1430, if you need more details, and I hope you don't).

I missed this a couple of months ago, but there was a paper withdrawn from the Journal of Organic Chemistry. The original is here, a contribution from the Indian Institute of Chemical Technology in Hyderabad on 2-aryl benzothiazoles.

The JOC editor's note is here, and states:

This manuscript was withdrawn from publication by the Editor-in-Chief of The Journal of Organic Chemistry. The basis for the withdrawal was a violation of the Ethical Guidelines to Publication of Chemical Research of the American Chemical Society. . .

The reason given is plagiarism from a paper in Angewandte Chemie in 2008, which is from Carsten Bolm's lab in Aachen on S-arylation of thiols. And here we find the trouble. Below are two sections - the first from the JOC paper, and the second from the original Ang. Chem.:

Among the various intramolecular reactions, S-arylation is comparatively less studied.(14) Two factors make this process difficult: First, thiols are prone to undergo oxidative S−S coupling reactions which result in the undesired formation of disulfides, and second, organic sulfur compounds can be effective metal binders, which leads to catalytic modification (or deactivation).(15) However, given the prevalence of C−S bonds in a wide range of pharmaceutically active compounds and polymeric materials,(16) it is desirable to find novel procedures that provide efficient access to such highly useful organic products.

Among the various cross-coupling types, S-arylation is comparatively less studied.[3] Two factors make this process difficult: First, thiols are prone to undergo oxidative SS coupling reactions, which result in the undesired formation of disulfides, and second, organic sulfur compounds can be effective metal binders, which leads to catalyst modification (or deactivation).[4] However, given the prevalence of CS bonds in a wide range of pharmaceutically active compounds and polymeric materials,[5] it is desirable to find novel catalytic procedures that provide efficient access to such highly useful organic products.

There's no doubt that this is a copy-and-paste job. And I believe that the ACS policy cited doesn't leave much wiggle room - if you do this, you get slapped down. What's silly about it is that it didn't have to happen. People borrow such background material all the time, to greater or lesser extents. But word for word? Bad idea. Frankly, if the Hyderabad authors had spent twenty minutes rewriting those sentences, no one would have ever noticed a thing. The automated similarity searches that can be done now (which I presume led to this incident) would have passed right over.

But (as far as I know) the conclusions of the JOC paper are still valid. And if you care about 2-arylbenzothiazoles, you might even want to see them. I note that the paper is still on the JOC web site, even though it's been "withdrawn". Is this the middle ground, then, a way to discipline people without yanking the results completely from the literature?

I had some requests to answer my own "Random Questions" from the other day, so here goes:

1. Does it bother you, or by contrast make you a bit proud, when you tell someone that you're a chemist and (as happens in about seven out of ten cases) they say "Oh, that was my hardest/least favorite/most boring subject when I was in school"?

Well, whether it bothers me or not, this happens all the time. Like pretty much every chemist in the world, I get to hear all about how people couldn't stand my subject in school. I take the point that mathematicians have it even worse, but it's not like we miss many of them with chemistry, either.

When people ask me what I do, I tell them "drug discovery", and I mention the diseases that I'm working on. That never fails to get some interest, and only then I spring on my listener the (often unexpected) info that this involves chemistry. Coming at it from that angle almost always leads to a good conversation, while coming at it from the "I'm a chemist" angle often leads to "Hey, look at the time!" effects. It's worth doing it in the right order, though - I like the effect when of showing that this boring/hard/useless subject actually leads to what most people find is a really interesting job.

2. How many thousands (10s, 100s of thousands) of dollars of unused equipment is sitting in dusty, unused storerooms at your company, because someone ordered it years ago and either (1) never got it to work, (2) was the only person ever to get it to work, or (3) found that it worked, but what it did wasn't worth doing that way?

Disused equipment? What is this disused equipment you speak of? Never have I seen such a thing. Why, those elaborate combichem machines in the sub-basement, they're just down there because they're so valuable. That rotating split-and-mix thingamabob and the multichannel parallel doohickey, we guard those closely.

Hah! Actually, I remember a couple of labs where this stuff wasn't in the basement at all. No, it was out there in the hoods, taking up space and slowly gathering dust, a standing reproach to everyone who walked past it. It would have been better off out of sight, but no one quite had the heart. And besides, it would sometimes get turned on for visiting groups - there was that.

3. Have you ever set up a reaction and thought "Boy, I sure hope that this doesn't work"?

I suppose that this is somewhat shameful, but yes, I have set up reactions hoping that they would fail. Usually it's been when I've had to use a particularly distasteful reagent (sodium ethanethiolate, for example), and I don't want to end up using it on a larger scale. I remember a fellow grad student presenting his work while we were trying to get our PhDs, and he detailed a deoxygenation step which only worked when his intermediate was made using a hefty excess of thiophosgene. "As fate would have it", said his long-suffering labmate from the back of the room.

And I've had less honorable instances, dating back to grad school or early in my industry career, when I was more or less forced to run a reaction a particular way even though I felt there was no chance for it to work. So yeah, in those cases I did look forward to saying "Yes, I tried your idea. And no, it didn't work any better than mine."

4. For the drug discovery people out there, what per cent of compounds you've made over the years would you guess dissolve in plain water to any real extent? Is that figure going up, or down?

The figure is hard to estimate, but it sure isn't high. Things that dissolve in straight water are hard to work with, y'know - they tend not to extract so well into ethyl acetate or dichloromethane, and they don't run so great on silica when you try to clean them up. That's worth another blog post in itself - the way that our standard chemistry techniques tend to push us away from a lot of polar molecules that might be just what we need for med-chem.

5. What, off the top of your head, would you say in retrospect is the most time-wasting chemistry you've ever ended up doing?

Tough competition. I'm tempted to say vacuum pyrolysis of corn starch to make levoglucosan, but I needed that for my dissertation, so it can't be called useless.

The real winner, in retrospect, has to be a series of reactions I did in my first couple of months in my grad school group, when I was still taking classes and working in the lab part time. I was presented with a route to a tetrahydropyran compound that we needed, a four-or-five stepper that involved an aluminum alkyne opening an epoxide, a Lindlar hydrogenation, a ring closure. . .I can still draw the damn thing on the board, now that I think about it, and it's been twenty-five years ago this spring. Being a first-year grad student, I hopped to it - and hopped right into the mud, since the route bogged down (and how) at the ring closure stage). I kept at it for a while, and then one evening I decided to look up my target compound in Chemical Abstracts.

That wasn't so easy in those stone ax and bearskin days - command-line access to CAS via a rockin' 1200 baud modem and a terminal was still a few months away. I paged through the five-year indices, and found. . .my compound. In a Tetrahedron paper. Two steps, from stuff you could buy from Aldrich, and you form the ring in the first step through a Prins reaction. I was shocked. Surely this couldn't be a known compound. Surely someone must have looked the structure up before coming up with that route I'd been given.

Surely not. And thus did my lab education begin. So you know, when I think about it, even though those first couple of months were a waste of chemicals and effort, perhaps they weren't as much a waste of time as I thought. . .

I didn't note it here when it came out last year, but I wanted to recommend this paper to all the readers who are medicinal chemists. It's an effort by M. Paul Gleeson of GSK to generalize some rules from huge piles of oral dosing data in the company's files. It's all boiled down to a set of charts, for different classes of compounds (neutral, acidic, basic, and zwitterionic), and you can see the effects of changing molecular weight and/or polarity on things like bioavailibility, potential for hERG problems, clearance, etc.

There are no major surprises in the charts. But it's very useful to have all these "rules of thumb" in one spot, and to have them backed up by plenty of data. For experienced medicinal chemists, it's a distillation of everything that we should have been learning. And for those starting out, it's a way to get a fast understanding of what matters when you're making new structures. Check it out!

Update: for a much more sceptical take, see here.

Here's a fascinating (and alarming) look at the clinical data from the recent trial of Avastin (bevacizumab) in adjuvant colorectal cancer (that is, post-surgical therapy). This was an issue in the recent Roche/Genentech takeover, since it could significantly enlarge the market for the drug. According to the In Vivo Blog, the one-year interim look at the data (adding Avastin to the standard chemotherapy regimen) was nearly good enough to stop the trial early. There were 2,710 patients enrolled, and an additional six events would have pushed things over the top, statistically.

The trial went on, though, with two more years of standard therapy as follow-up. But by the (pre-set) three-year endpoint it turned out that there was no eventual real benefit to adding Avastin back in that first year. So what's the story? Is it that you need to keep giving the combination regime? Would those-one year results have held up? Or is this just a case of real long-term survival numbers wiping out what seems to be a promising short-term result?

It looks like Genentech may be gearing up to put that first theory to a test, and I wish them luck. Long-term tolerability will be an issue, and long-term cost will be a big one, too. They're going to have to show some pretty impressive numbers to overcome those two concerns. . .as impressive as, well, as those first-year interim ones they had. Will that effect dissipate or not?

Time and money will answer that little question. But for now, consider what would have happened if a few more patients had shown disease-free survival in time for that interim analysis. The trial would have been stopped early, all kinds of people would have gone on Avastin for their first year of adjuvant therapy. . .and this year we would have seen that it was apparently doing no good at all, at least in the take-it-for-a-year-and-stop mode. Clinical trial design: a real high-wire act.