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

Derek Lowe The 2002 Model

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

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

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October 31, 2012

Oops. We Didn't Mean to Publish That.

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Posted by Derek

Here's an interesting situation, courtesy of Retraction Watch - trying to pull back a paper because it disclosed something that was supposed to be the subject of your patent. Say the authors of the paper in the Korean Journal of Physiology and Pharmacology:

We regret to inform that the published paper included a few parts that disclosed confidential information which should have been protected under patent law. We admit that the request for retraction is due to the indiscretion of the authors, and confirmed that editorial committee of KJPP have not conducted any fault in publishing the paper.

I would think that if you've disclosed, you've disclosed, so this will all come down to timing. Shouldn't matter much whether the paper has been retracted or not. . .

Comments (8) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature

The Coming Battle Over Alzheimer's Disease

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Posted by Derek

Solanezumab is a story that won't go away. Eli Lilly's antibody therapy for Alzheimer's is the subject of a lot of arguing among investors: some people (and I'm one of them) think that there is no strong evidence for its efficacy, not yet, and that the amount of time and effort devoted to finding that out means that there likely isn't any meaningful efficacy to be found. Others are more optimistic, which is why Lilly's stock has risen in recent months.

The latest point of contention is an independent analysis of biomarker data which came out this week at a conference in Monaco. This suggests that there was a meaningful change in the amount of circulating beta-amyloid after treatment, which could mean that the antibody was working as planned to increase clearance of soluble amyloid, thus altering the amyloid balance in the CNS. It should be noted that this line of attack depends on several factors - first among them, that amyloid is a causative factor in Alzheimer's, and secondly, that clearing it from the periphery can affect its concentration and distribution inside the brain. There's evidence for both of these, and there's evidence against both of them. Such questions can only be answered in the clinic, and I'm glad that Lilly, Roche/Genentech, and others are trying to answer them.

What I want to focus on today, though, is an issue that comes up in passing in the Fierce Biotech link above:

Biomarkers and pooled data may help support further studies of the drug, as well as other programs that rest on the beta amyloid hypothesis, but they don't prove that solanezumab works as hoped. Nevertheless, the first sign of success in this field has fueled tremendous enthusiasm that something in the pipeline could eventually work--perhaps even pushing regulators to approve new therapies with something less than clear efficacy data. And any newly approved drug would find a massive market of millions of desperate patients.

That's a big "perhaps", one that's worth tens of billions of dollars. What I worry about is pressure building for the FDA to approve an Alzheimer's therapy (solanezumab or something else) based on these hints of mechanistic efficacy. The problem is, solanezumab hasn't shown much promise of improving the lives of actual Alzheimer's patients. Lilly's own trials showed a possible improvement in a measure of cognitive decline, but this did not show up again in a second patient group, even when they specifically modified the endpoints of the trial to look for it. And neither group showed any functional effects at all, which I think are what most Alzheimer's patients (and their family members) would really want to see.

But there really is such a huge demand for something, anything, with any hint of hope. People would line up to buy anything that got FDA approval, no matter how tenuous the evidence was. And that puts the agency in a very tough position, similar to the one it was in with the Avastin breast cancer issue. Update: there was, to be sure, more of a safety question with Avastin at the same time. You can argue that one of the main purposes of the agency is to make sure that medicines that people can be prescribed in this country will actually do some good, rather than raise hopes for nothing. You could also argue that responsible adults - and their physicians, and their insurance companies - should be able to make such choices for themselves, and should be able to spend their time and money in the ways that they best see fit. You could argue that companies with marginally effective (or ineffective) therapies face a huge moral hazard, in that their incentives are to get such treatments onto the market whether they do anyone else any good or not. None of these are foolish positions, but they are also, in places, mutually incompatible. Alzheimer's disease might well turn into the next place in which we thrash them out.

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Prices | Regulatory Affairs

October 30, 2012

JQ1: Giving Up a Fortune?

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Posted by Derek

The Atlantic is out with a list of "Brave Thinkers", and one of them is Jay Bradner at Harvard Medical School. He's on there for JQ1, a small-molecule bromodomain ligand that was reported in 2010. (I note, in passing, that once again nomenclature has come to the opposite of our rescue, since bromodomains have absolutely nothing to do with bromine, in contrast to 98% of all the other words that begin with "bromo-")

These sorts of compounds have been very much in the news recently, as part of the whole multiyear surge in epigenetic research. Drug companies, naturally, are looking to the epigenetic targets that might be amenable to small-molecule intervention, and bromodomains seem to qualify (well, some of them do, anyway).

At any rate, JQ1 is a perfectly reasonable probe compound for bromodomain studies, but it got a lot of press a couple of months ago as a potential male contraceptive. I found all that wildly premature - a compound like this one surely sets off all kinds of effects in vivo, and disruption of spermatogenesis is only one of them. Note (PDF) that it hits a variety of bromodomain subtypes, and we only have the foggiest notion of what most of these are doing in real living systems.

The Atlantic, for its part, makes much of Bradner's publishing JQ1 instead of patenting it:

The monopoly on developing the molecule that Bradner walked away from would likely have been worth a fortune (last year, the median value for U.S.-based biotech companies was $370 million). Now four companies are building on his discovery—which delights Bradner, who this year released four new molecules. “For years, drug discovery has been a dark art performed behind closed doors with the shades pulled,” he says. “I would be greatly satisfied if the example of this research contributed to a change in the culture of drug discovery.”

But as Chemjobber rightly says, the idea that Bradner walked away from a fortune is ridiculous. JQ1 is not a drug, nor is it ever likely to become a drug. It has inspired research programs to find drugs, but they likely won't look much (or anything) like JQ1, and they'll do different things (for one, they'll almost surely be more selective). In fact, chasing after that sort of selectivity is one of the things that Bradner's own research group appears to be doing - and quite rightly - while his employer (Dana-Farber) is filing patent applications on JQ1 derivatives. Quite rightly.

Patents work differently in small-molecule drug research than most people seem to think. (You can argue, in fact, that it's one of the areas where the system works most like it was designed to, as opposed to often-abominable patent efforts in software, interface design, business methods, and the like). People who've never had to work with them have ideas about patents being dark, hidden boxes of secrets, but one of the key things about a patent is disclosure. You have to tell people what your invention is, what it's good for, and how to replicate it, or you don't have a valid patent.

Admittedly, there are patent applications that do not make all of these steps easy - a case in point would be the ones from Exelixis - I wrote here about my onetime attempts to figure out the structures of some of their lead compounds from their patent filings. Not long ago I had a chance to speak with someone who was there at the time, and he was happy to hear that I'd come up short, saying that this had been exactly the plan). But at the same time, all their molecules were in there, along with all the details of how to make them. And the claims of the patents detailed exactly why they were interested in such compounds, and what they planned to do with them as drugs. You could learn a lot about what Exelixis was up to; it was just that finding out the exact structure of the clinical candidate that was tricky. A patent application on JQ1 would have actually ended up disclosing most (or all) of what the publication did.

I'm not criticizing Prof. Bradner and his research group here. He's been doing excellent work in this area, and his papers are a pleasure to read. But the idea that Harvard Medical School and Dana-Farber would walk away from a pharma fortune is laughable.

Comments (33) + TrackBacks (0) | Category: Cancer | Chemical Biology | Drug Development | Patents and IP

Back On the Air

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Posted by Derek

Over here to the west of Boston, we had a real storm - downed tree branches all around my neighborhood, power outages - but fortunately nothing like what they had further south of here, starting in Connecticut and really picking up in New York and New Jersey. So it's back to work, on the somewhat-delayed MBTA, and back to blogging on the train! I hope that readers on the East Coast made it through OK (and people on towards the Great Lakes, too, since I see that this is hitting in Cleveland and Detroit as well). What a mess.

Comments (8) + TrackBacks (0) | Category: Blog Housekeeping

October 29, 2012

Blogging Outage

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Posted by Derek

Well, all of us in the Northeast are battening down today for the storm, and a lot of companies and research labs either didn't open or are closing early. In that world, my sympathies go out to the people in the cell culture labs and the animal facilities, who can't just shut off the stir plates and go home immediately for the duration. Running those labs is like having a lot of very demanding pets, but ones that can cost you huge sums of money and time if they become unhappy. Good luck to everyone, and here's hoping that the maintenance on all those backup generators was actually kept up! Regular blogging will resume tomorrow. . .

Comments (12) + TrackBacks (0) | Category: Blog Housekeeping

October 26, 2012

Accident Report, or One Damn Thing After Another

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Posted by Derek

I have this from a lab-accidents-I-have-known discussion over on Reddit. It is, of course, unverified, but it's depressingly plausible. As a chemist, this one is guaranteed to make you bury your head in your hands - it's the second law of thermodynamics come to take vengeance, with the entropy increasing as you go along:

"A graduate student was constructing three solvent stills (dichloromethane, THF and toluene) inside a hood in Room XXXX. As a final step in this process, the student was cutting pieces of sodium metal to add to the stills. Once the sodium had been added, the student began to clean the knife used to cut the sodium. During the cleaning, a small particle of sodium was apparently brushed off the knife. The sodium landed in a drop of water/wet spot on the floor of the hood and reacted immediately making a popping sound. The graduate student was startled by this sound and moved away quickly.

In his haste to get away from the reacting sodium, he discarded the knife into a sink on the bench opposite the hood in which he was working.. Apparently, there was another piece of sodium still adhering to the knife since upon being tossed into the sink, a fire ignited in the sink, catching the attention of another student in the lab. As the flames erupted, the student noticed a wash bottle of acetone sitting on the sink ledge nearby. He immediately grabbed it to get it away from the flames, but in the process, squeezed the bottle, which squirted out some acetone which immediately ignited. The student immediately dropped the bottle and began to evacuate the lab. As he turned to leave, he knocked over a five gallon bucket containing an isopropanol/potassium hydroxide bath which also began to burn. This additional fire caused the sprinklers to activate and the fire alarm to sound which in turn resulted in the evacuation of the building.

When the sprinklers activated, water poured into the bulk sodium-under-mineral-oil storage bottle which had been left uncapped in the hood resulting in a violent reaction which shattered the bottle sending more sodium and mineral oil into the sprinkler water stream. This explosion also cracked the hood safety glass into numerous little pieces although it remained structurally intact. By the time the first-responders arrived on the scene, the fire had been extinguished by the sprinklers, but numerous violent popping sounds were still occurring. The first-responders unplugged the electrical cords feeding the heating mantles, shut off the electricity to the room at the breaker panel and waited until the Fire Department arrived. Eventually the popping noises stopped and sprinklers were turned off. The front part of the lab sustained a moderate amount of water damage The hood where the incident began also suffered moderate damage and two of the three still flasks were destroyed. The student, who was wearing shorts at the time of this accident, sustained second and third-degree burns on his leg as a result of the fire involving the isopropanol base bath.

There were some additional injuries incurred by the first-responders who unexpectedly slipped and fell due to the presence of KOH from the bath in the sprinkler water. These injuries were not serious but they do illustrate the need to communicate hazards to first-responders to protect them from unnecessary injury."

I doubt if the sodium was being added to the dichloromethane still; I've always heard that that's asking for carbene trouble. (Back in my solvent-still days, we used calcium hydride for that one). And it would take a good kick to knock over a KOH/isopropanol bath, but no doubt there was some adrenaline involved. I'm also sorry to hear about the burns sustained by the graduate student involved, but this person should really, really have not been wearing shorts, just as no one should in any sort of organic chemistry lab.

But holy cow. The mental picture I have is of Leslie Neilsen in a lab coat, rehearsing a scene for another "Naked Gun" sequel. This is what happens, though, when things go bad in the lab: we've all got enough trouble on our benches and under our fume hoods to send things down the chute very, very quickly under the wrong conditions. And were these ever the wrong conditions.

Comments (55) + TrackBacks (0) | Category: Graduate School | How Not to Do It | Safety Warnings

"Basically, They're A Bunch of Lemmings"

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Posted by Derek

True, but that's unfair to lemmings. This is Raghuram Selveraju of Aegis Capital, talking about deal-making executives in the big pharma companies and the string of costly blowups so far this year. That link has the list, and it's quite an impressive string of fireballs.

“What all of these deals had in common was the desperation of big pharma, because its R&D productivity has been dropping and we’ve known that for a long time,” he said.

That desperation leads to the repetition of familiar mistakes which derive from the predictable thinking of too many business development executives at big pharma, Selveraju opined. First, when looking for licensing opportunities, pharmas very often seek out their comfort zone – a potential product for which they can deploy an existing sales force or promote to doctors they already know and communicate with. Also, to be confident in an experimental drug’s preclinical and clinical data, pharmas often want to go into areas where their competitors also have a compound as well as into validated targets.

“Basically, they’re a bunch of lemmings,” Selveraju said. “As soon as a target becomes hot, they all have to have a molecule in that space, hitting that target."

But who could blame them? Going out into areas that haven't been explored, or haven't worked out for others, can get you slaughtered, too (ask Eli Lilly about Alzheimer's). And when that happens, you have nowhere to hide. If everyone else was rushing into a given therapeutic area and it turns out to be a disaster, well, you yourself might be able to get by, because that's just one of those things, and it happened to everyone at the same time. It reminds me of something I saw years ago about investment managers. If you go out and buy a bunch of (say) IBM for your clients and it drops, people might say "Man, what's wrong with IBM?" But if you go out and buy a bunch of WhoZat, Inc., and it drops, people will ask what's wrong with you.

My own biases make me think that if the chances for failure are high both ways, then maybe you should go ahead and strike out for the unknown territory, because the payoff is larger if you succeed. Selveraju himself has a much more cautious (and perhaps outright dispiriting) recommendation:

What then is Selveraju’s prescription for better business development practices? It might disappoint those who want pharma to be in the vanguard of innovation. He recommends incremental innovation – using FDA’s 505b2 pathway to develop products with already defined efficacy and safety – as well as biosimilars and re-purposing. Pharma also should focus on niche and specialty indications, and largely eliminate primary care products and the large commercial operations that come with them.

That's cranking up the dial even more on the Bernard Munos strategy. Munos also recommends getting out of the big, expensive areas and going more for niche and specialty ones, but mainly because of the cost of the clinical trials (and the validation step inherent in them). Alzheimer's, for example, scores big on innovation, but very, very poorly on the risk/cost ratio, since it's going to take you years and years in huge clinical trials to see if you've got something.

But that "develop products with already defined efficacy and safety" line is Selveraju’s own, and doesn't that sound like loads of fun? Coming up with new formulations and dosing schedules of existing drugs is what a 505(b)(2) strategy amounts to, and it brings up thoughts of alternative careers - going off to trucking school and learning to drive the big rigs, for example. Actually, as a drug-discovery chemist, that's probably what I'd end up doing if everyone switched to that plan, since you certainly don't need people like me if you're five-oh-five-bee-twoing.

Comments (21) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Regulatory Affairs

October 25, 2012

Travel (For C&E News)

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Posted by Derek

I'm in Washington today for a meeting of the C&E News editorial board (which I believe is the last one I'll be attending during my term on it). I'll be able to check the blog during the day for comments, but I don't know if I'll have time to put up a post until later on this afternoon. (In theory, I should be downstairs right now, having breakfast!)

But anyone with thoughts on the magazine, its news coverage, and what you as a reader might want to see more or less of in it, please add your comments. I can assure you that the staff will see them!

Comments (39) + TrackBacks (0) | Category: Blog Housekeeping

October 24, 2012

Too Many Med Chem Journals?

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Posted by Derek

The recent discussions on awful molecules in the med-chem literature got me to thinking the other day. There are many more med-chem journals now than there used to be. Back in the day, you had the Journal of Medicinal Chemistry, and that was that. Then in the early 1990s came Bioorganic and Medicinal Chemistry and Bioorganic and Medicinal Chemistry Letters. Now we've got ACS Medicinal Chemistry Letters and MedChemComm and ChemMedChem, among others. (And as we were seeing the other day, there are levels and levels as you move down, ranging from obscure-but-respectable, to just plain obscure, all the way to disreputable crap).

This at a time when industrial medicinal chemistry has been getting cut back. Now, on the other side of the ledger, you have all the folks who are cleaning out the file cabinets for publishable material to have on their C.V.s (and don't think that's not a real force). But in general, I have to wonder if the amount of medicinal chemistry being published from industry hasn't been going down.

Here, then is the question: is there enough decent medicinal chemistry being done to usefully fill all the pages of all these journals? My answer, as you might guess, is "Probably not". But I'd welcome other opinions.

Comments (20) + TrackBacks (0) | Category: The Scientific Literature

The Onion on Oncology Research

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Posted by Derek

I'd say they have it pretty close to reality:

". . .a new Mayo Clinic study with widespread implications for the treatment and potential cure of the disease has found that the malignant growths have begun cruelly mocking researchers. 


The findings—published this week in a rambling, expletive-laden 8,000-word article in The Journal Of The American Medical Association—provides the strongest evidence yet that abnormal cells targeted with cutting-edge cancer treatments are basically flipping off scientists left and right, and get a huge kick out of making oncologists feel like a bunch of bumbling dipshit chumps.

I feel that way about my reactions sometimes. And there were a few points during my PhD when I felt that the only explanation for the way things were going was the existence of a malignant force in the universe, one that for reasons beyond my comprehension was taking a personal interest in me.

Comments (12) + TrackBacks (0) | Category: Cancer

Chem Coach Carnival: A Few Questions

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Posted by Derek

Over at Just Like Cooking, See Arr Oh has been organizing a "Chem Coach Carnival". He's asking chemists (blogging and otherwise) some questions about their work, especially for the benefit of people who don't do it (or not yet), and I'm glad to throw an entry into the pile:

Describe your current job
My current job is titled "Research Fellow", but titles like this are notoriously slippery in biotech/pharma. What I really do is work in very early-stage research, pretty much the earliest that a medicinal chemist can get involved in. I help to think up new targets and work with the biologists to get them screened, then work to evaluate what comes out of the screening. Is it real? Is it useful? Can it be advanced? If not, what other options do we have to find chemical matter for the target?

What do you do in a standard "work day?"
My work day divides between my office and my lab. In the office, I'm digging around in the new literature for interesting things that my company might be able to use (new targets, new chemistry, new technologies). And I'm also searching for more information on the early projects that we're prosecuting now: has anyone else reported work on these, or something like them? And there are the actual compound series that we're working on - what's known about things of those types (if anything?) Have they ever been reported as hits for other targets? Any interesting reactions known for them that we could tap into? There are broad project-specific issues to research as well - let's say that we're hoping to pick up some activity or selectivity in a current series by targeting a particular region of our target protein. So, how well has that worked out for other proteins with similar binding pockets? What sorts of structures have tended to hit?

In the lab, I actually make some of the new compounds for testing on these ongoing projects. At this stage in my career (I've been in the industry since 1989), my main purpose is not cranking out compounds at the bench. But I can certainly contribute, and I've always enjoyed the physical experience of making new compounds and trying new reactions. It's a good break from the office, and the office is a good break from the lab when I have a run of discovering new ways to produce sticky maroon gunk. (Happens to everyone).

This being industry, there are also meetings. But I try to keep those down to a minimum - when my calendar shows a day full of them, I despair a bit. Most of the time, my feelings when leaving a meeting are those of Samuel Johnson on Paradise Lost: "None ever wished it longer".

Note: I've already described what happens downstream of me - here's one overview.

What kind of schooling / training / experience helped you get there?
I have a B.A. and a Ph.D., along with a post-doc. But by now, those are getting alarmingly far back in the past. What really counts these days is my industrial experience, which is now up to 23 years, at several different companies. Over that time, I don't think I've missed out on a single large therapeutic area or class of targets. And I've seen projects fail in all sorts of ways (and succeed in a few as well) - my worth largely depends on what I've learned from all of them, and applying it to the new stuff that's coming down the chute.

That can be tricky. The failings of inexperience are well known, but experience has its problems, too. There can be a tendency to assume that you really have seen everything before, and that you know how things are going to turn out. This isn't true. You can help to avoid some of the pitfalls you've tumbled into in the past, but drug research is big enough and varied enough that new ones are always out there. And things can work out, too, for reasons that are not clear and not predictable. My experience is worth a lot - it had better be - but that value has limits, and I need to be the first person to keep that in mind.

How does chemistry inform your work?
It's the absolute foundation of it. I approach biology thinking like a chemist; I approach physics thinking like a chemist. One trait that's very strong in my research personality is empiricism: I am congenitally suspicious of model systems, and I'd far rather have the data from the real experiment. And those real experiments need to be as real as possible, too. If you say enzyme assay, I'll ask for cells. If you have cell data, I'll ask about mice. Mice lead to dogs, and dogs lead to humans, and there's where we really find out if we have a drug, and not one minute before.

In general, if you say that something's not going to work, I'll ask if you've tried it. Not every experiment is feasible, or even wise, but a surprising amount of data gets left, ungathered, because someone didn't bother to check. Never talk yourself out of an easy experiment.

Finally, a unique, interesting, or funny anecdote about your career
People who know me, from my wife and kids to my labmates, will now groan and roll their eyes, because I am a walking collection of such things. Part of it's my Southern heritage; we love a good story well told. I think I'll go back to grad school for this one; I'm not sure if I've ever told it here on the blog:

When I first got to Duke, I was planning on working for Prof. Bert Fraser-Reid, who was doing chiral synthesis of natural products using carbohydrate starting materials. In most graduate departments, there's a period where the new students attend presentations by faculty members and then associate themselves with someone that they'd like to work for. During this process, I wanted to set up an interview with Fraser-Reid, so I left a note for him to that effect, with my phone number. His grad students told me, though, that he was out of town (which was not hard to believe; he traveled a great deal).

That night I was back in my ratty shared house off of Duke's East Campus, which my housemates and I were soon to find out we could not afford to actually heat for the winter (save for a coal stove in the front room). And at 9 PM, I was expecting a call from a friend of mine at Vanderbilt, a chemistry=major classmate of mine from my undergraduate school (Hendrix) who knew that I was trying to sign up with Fraser-Reid's group. So at 9 PM sharp, the phone rings, and I pick it up to hear my friend's voice, as if through a towel held over the phone, saying that he was Dr. Fraser-Reid, at Duke.

Hah! Nice try. "You fool, he's out of town!" I said gleefully. There was a pause at the other end of the line. "Ah, is this Derek Lowe? This is Dr. Fraser-Reid, at Duke." And that's when it dawned on me: this was Dr. Fraser-Reid. At Duke. One of my housemates was in the room while this was going on, and he told me that he'd thought until then that watching someone go suddenly pale was just a figure of speech. The blood drained from my brain as I stammered out something to the effect that, whoops, uh, sorry, I thought that he was someone else, arrgh, expecting another call, ho-ho, and so on. We did set up an appointment, and I actually ended up in his group, although he should have known better after that auspicious start. This particular mistake I have not repeated, I should add. Ever restless and exploring, I have moved on to other mistakes since then.

Comments (7) + TrackBacks (0) | Category: General Scientific News | Graduate School | Life in the Drug Labs

October 23, 2012

Improving Half-Life

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Posted by Derek

There was a question in the comments from a reader who's picking up med-chem, and I thought it was worth answering out here. I've been meaning to shore up the "Pharma 101" category, and this is a good opportunity. So how, in a case like that compound in the previous post, do you increase a compound's half-life?

The first thing to do is try to figure out why it's so short. That's almost certainly due to the compound being metabolized and excreted - once in a while, you'll find a compound that quietly partitions into some tissue and hides out, but for the most part, a disappearing compound is getting chewed up and spit out. For one that's being injected like this, you'd want to look in the blood for metabolites, and in the urine for those and the parent compound, and try to see how much you can account for. No point in checking feces or the bile contents - if this thing were dosed orally, though, you'd definitely not ignore those possibilities.

Looking for metabolites is something of a black art. There are plenty of standard things to check, like the addition of multiples of 16 (for oxidations). Examination of the structure can give you clues as well. I'd consider what pieces I'd see after cleavage of each of those amide bonds, for example, and look for those (and their oxidation products). The bromine and iodine will help you track things down in the mass spec, for sure. That phenol over on the right-hand side is a candidate for glucuronidation (or some other secondary metabolite), either of the parent or some piece thereof, so you'd want to look for those. Same thing could happen to some of the free acids after cleavage of the amides. And I have no idea what that difluorophosphonate does, but I'd be rooting through the PK literature to find out what such things have done in the past.

If you can establish some major metabolic routes, then you can think about hardening the structure. What if some of those amides are N-methylated, for example? Can you do that without killing the binding? Would putting another atom on the other side of the phenol affect its conjugation? There are all sorts of tricks, mostly involving steric hindrance and/or changing electron density around some hot spot.

Update: a commenter notes that I've left out prodrugs, and that's quite right. A prodrug is a sort of deliberate metabolism. You put in a group that gets slowly cleaved off, liberating the active compound - esters are a favorite strategy of this sort. Much of the time, a prodrug is put on to improve the solubility and/or absorption of a compound (that is, something polar and soluble grafted onto a brick), but they can certainly influence half-life, too.

The other major strategy is formulation. If you really can't shore up your structure, or if that isn't enough, then you can think about some formulation that'll deliver your compound differently. Would some sort of slow-release help? These things are trickier with injectables than they are with oral medications, from what experience I've had, but there are still things that can be done.

So that's a short answer - there are, of course, a lot of details involved, and a lot of tricks that have been developed over the years. But that's one way to start.

Comments (16) + TrackBacks (0) | Category: Pharma 101 | Pharmacokinetics

Huge But Effective

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Posted by Derek

Of the physical properties that make up the "Rule of Five" (and similar schemes), the one that I think is easiest to breach is molecular weight. I'm not saying that it's a good idea to breeze past 500 daltons with a song on your lips - you should always realize that you're probably asking for trouble up there. But trouble seems to follow a bit less often than it does with, say, a high logP. For a high-value target, I think it's certainly worth pursuing if that's really where you have to go.

Here's a whopper of a molecule, for example, an inhibitor of PTP-MEG2 (also known as PTPN9). That's an unusual phosphatase involved in hepatic insulin signaling, and it's already been shown that knocking it down seems to be beneficial in diabetic rodent models. But, like another longtime diabetes target in this space (PTP1B), it's not easy to get a decent inhibitor. Phosphatases are tricky. Their active sites are very polar (as you'd imagine, having to work with phosphate anions all day), and there aren't all that many phosphatase subtypes as you'd expect, given the amount of such work there is to do. That leads to worries about selectivity, even should you find a molecule that seems to work.
Compound%207.png
So if you can't find a decent inhibitor, how about an indecent one? That's the first reaction on seeing the structure at left. You can certainly see its resin-bound peptidomimetic library roots. I only wish the authors had found a way to incorporate a chlorine atom somewhere; it would have been one of the rare compounds that runs the table on the halogens. As it is, this floating island weighs 1084, well beyond what anyone could consider reasonable for a drug candidate.

It's selective, naturally. Something this size is making so many interactions that its chances of fitting in a lot of different places is quite small. (There's a crystal structure, which doesn't appear to be showing up in the PDB as yet). It's got a Ki of 34 nanomolar against its target, and about 600 for PTP-TC and PTP1B. All the other protein tyrosine phosphatases are dead, and I'd be very surprised if it hits something from another class. But selectivity isn't the hurdle for these leviathans - it's pharmacokinetics. And here we have a surprise.

First off, the compound shows good activity in mouse heptatocytes, and in other insulin-sensitive cell lines. That's quite interesting, since PTP-MEG2 is surely intracellular - so what part of the cell membrane is letting Godzilla through the turnstiles? The authors moved on to i.p. injection in mice, and found that at at 20 mpk level the compound hit a Cmax of 4.5 micromolar (pretty respectable, considering that molecular weight), and had a half-life of 1.8 hours. That's short, but not as short as one might have feared. Multiday treatment of mice showed just the sorts of on-target effects that one might have predicted: inhibition of hepatic gluconeogenesis, enhanced glucose clearance and insulin sensitivity. That's just the sort of profile you'd want for a Type II diabetes drug, and with a bit of work on the half-life, you might have one here as an injectable. I don't hold out much hope for oral activity with a molecule like this, but it's impressive that it gets this far, and it provides some real proof-of-concept for PTP-MEG2 as a drug target.

So in case anyone's wondering whether I can say anything kind about tool compounds, or about academic drug discovery (this paper's from Indiana U), well, here's your evidence. I don't know whether the authors were brave or just foolhardy to consider these structures, but they've latched onto something worthwhile.

Comments (21) + TrackBacks (0) | Category: Diabetes and Obesity

October 22, 2012

March of the Ugly Tool Compounds

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Posted by Derek

The recent discussions here about ugly tool compounds have prompted an alert reader to send in this example, a putative agonist of the orphan receptor GPR35. Will someone rise to the defense of this one?

Comments (22) + TrackBacks (0) | Category: Chemical News

The Absolute Bottom of the Publishing Barrel

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Posted by Derek

Every so often, you come across scientific journals that you've absolutely, completely never heard of. Back in graduate school (mid-1980s for me), I used to keep track of the weirdest references that came up - Journal of the Siberian Oil Chemist's Society, or Bulletin of the Kentucky Academy of Sciences (1954), which I think you'd have a hard time laying your hands on even in Kentucky. Then there are all the obscure "flag carrier" journals. One that shows up fairly often in searches for odd heterocyclic systems in the Egyptian Journal of Chemistry, but there are others that I have never seen a reference to in nearly 30 years of looking at the chemical literature, such as the Revista Colombiana de Quimica. Europe used to be covered with national chemistry titles, most of which have ceased publication or were merged into Chem. Eur. J. or the like. But some of the newly independent countries were glad to start up their own literature, so you have (for example) the Journal of the Serbian Chemical Society.

Now, I have no wish to offend any Serbian readership I may have, but I will not be bringing any unexpected news if I point out that JSCS is not the most prestigious venue available. In the old days, such a title would be full of local papers, and to be sure, there are plenty of manuscripts from Belgrade. But there are also plenty from places like Brazil, Iran, Egypt, Pakistan, and (naturally) the further corners of India and China. I suspect that some authors from these countries get to count such papers as having been published in a European scientific journal, as opposed to the less-impactful venues closer to home. There is, for example, an Iranian Journal of Chemistry and Chemical Engineering, as there is a Journal of the Brazilian Chemical Society.

But these days, there's a much larger and fuzzier category of obscure journal, and we have the internet and the idea of open access to thank for them. Well, those and greed. If I had to pick, I'd say that greed is the main factor. I'm talking about scam publishing, the dozens upon dozens of "open access" journals that have sprung up that (1) accept everything, and (2) charge a significant publication fee. That money is supposed to cover the costs of editorial work and open access on publication - and such fees can be completely legitimate, of course. But in the case of these publishers, it's a scam, since there are very, very few costs involved. No one edits these papers to any significant degree, and to a good approximation, no one ever accesses the papers, either. Bandwidth charges are thus held down to manageable levels.

Here's a good resource on these outfits, Beall's List of Predatory Open-Access Publishers. Jeffrey Beall of the University of Colorado-Denver has compiled a list of shady operations, most of which are characterized by suspiciously vast lists of titles and hefty publication charges. The one publisher on the list that you might have heard of is Bentham Open, the "open-access" arm of Bentham Publishing. I've always considered their regular list of journals to be pretty borderline stuff, although they have published some useful reviews. But Beall characterizes Bentham Open as "a scholarly vanity press", and that seems pretty accurate.

Take, for example, their Open Medicinal Chemistry Journal. It appears to have published two papers so far this year. Last year, it put out a special issue on "Medicinal Chemistry of Novel Anti-Diabetic Drugs", which sounds interesting until you note that there are three papers therein: a leadoff editorial (from an author at the University of the United Arab Emirates), a paper from that editorial writer and several collaborators (four authors, four countries), and still another paper from him and one of the authors of the first paper. Hmm.

Now, the scholarly worth of such things can be debated. They're of little immediate interest, but if the results contained are real, then they are, presumably, tiny bricks in the great edifice of scientific knowledge, and might conceivably be useful to someone, someday. From that standpoint, I don't have much room to criticize them. But since I've said many unkind things about the established scientific publishing houses and their business models, it's only fair that I point out that some of the untraditional ones are just as rapacious. The sorts of "journals" on Beall's list are not even pretending to add anything to the store of human knowledge: they're publication mills, turning anything you want to pay for into a "scientific paper". Some (not all) of the authors may deserve sympathy, by virtue of their obscure, unfunded origins (although they must have enough funds to pay for these papers), but the publishers deserve none at all for taking advantage of them. And when they're not taking advantage of ignorance and/or desperation, then the transaction is a cynical one indeed, reminding me of the old joke from the Soviet Union that went "As long as they pretend to pay me, I'll pretend to work".

Will they really publish anything? Why, yes, they will, as a mathematician proved by submitting a paper full of incoherent gibberish and getting it accepted. He used MathGen, a modified version of the random-paper generator SciGen that I've written about here. You'd think that the institutional address of "University of Southern North Dakota at Hoople" would tip someone off, but there are no P.D.Q. Bach fans in that audience.

Comments (27) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

October 19, 2012

Another Controversial Scaffold?

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Posted by Derek

My post the other day on a very unattractive screening hit/tool compound prompted a reader to mention this paper. It's one from industry this time (AstraZeneca), and at first it looks like similarly foul chemical matter. But I think it's worth a closer look, to see how they dealt with what they'd been given by screening.
PIM%20hit.png
This team was looking for hits against PIM kinases, and the compound shown was a 160nM hit from high-throughput screening. That's hard to ignore, but on the other hand, it's another one of those structures that tell you that you have work to do. It's actually quite similar to the hit from the previous post - similar heterocycle, alkylidene branching to a polyphenol.

So why am I happier reading this paper than the previous one? For one, this structure does have a small leg up, because this thiazolidinedione heterocycle doesn't have a thioamide in it, and it's actually been in drugs that have been used in humans. TZDs are certainly not my first choice, but they're not at the bottom of the list, either. On the other hand, I can't think of a situation where a thioamide shouldn't set off the warning bells, and not just for a compound's chances of becoming a drug. The chances of becoming a useful tool compound are lower, too, for the same reasons (potential reactivity / lack of selectivity). Note that these compounds are fragment-sized, unlike the diepoxide we were talking about the other day, which means that they're likely to be able to fit into more binding sites.

But there's still that aromatic ring. In this case, though, the very first thing this paper says after stating that they decided to pursue this scaffold is: "We were interested to determine whether or not we could remove the phenol from the series, as phenols often give poor pharmacokinetic and drug-like properties.". And that's what they set about doing, making a whole series of substituted aryls with less troublesome groups on them. Basic amines branching off from the ortho position led to very good potency, as it turned out, and they were able to ditch the phenol/catechol functionality completely while getting well into (or below) single-digit nanomolar potency. With these compounds, they also did something else important: they tested the lead structures against a panel of over four hundred other kinases to get an idea of their selectivity. These is just the sort of treatment that I think the Tdp-1 inhibitor from the Minnesota/NIH group needs.

To be fair, that other paper did show a number of attempts to get rid of the thioamide head group (all unsuccessful), and they did try a wide range of aryl substituents (the polyphenols were by far the most potent). And it's not like the Minnesota/NIH group was trying to produce a clinical candidate; they're not a drug company. A good tool compound to figure out what selective Tdp-1 inhibition does is what they were after, and it's a worthy goal (there's a lot of unknown biology there). If that had been a drug company effort, those two SAR trends taken together would have been enough to kill the chemical series (for any use) in most departments. But even the brave groups who might want to take it further would have immediately profiled their best chemical matter in as many assays as possible. Nasty functional groups and lack of selectivity would surely have doomed the series anywhere.

And it would doom it as a tool compound as well. Tool compounds don't have to have good whole-animal PK, and they don't have to be scalable to pilot plant equipment, and they don't have to be checked for hERG and all the other in vivo tox screens. But they do have to be selective - otherwise, how do you interpret their results in an assay? The whole-cell extract work that the group reported is an important first step to address that issue, but it's just barely the beginning. And I think that sums up my thoughts when I saw the paper: if it had been titled "A Problematic Possible Tool Compound for Tdp-1", I would have applauded it for its accuracy.

The authors say that they're working on some of these exact questions, and I look forward to seeing what comes out of that work. I'd have probably liked it better if that had been part of the original manuscript, but we'll see how it goes.

Comments (19) + TrackBacks (0) | Category: Academia (vs. Industry) | Chemical News

October 18, 2012

Layoffs at Human Genome Sciences

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Posted by Derek

Like night follows day: GSK completes its acquisition of HGS, and the scythe begins to come down. The company had previously notified the state of Maryland that it was cutting 114 positions, and now it's saying that 97 more are disappearing. That Fierce Biotech post says that even more are on the way after the first of the year.

GSK had offered $13 a share for the company, which the company turned down as too low. They got $14.25 in the end, which is not the sort of premium that they'd been hoping for, I'm sure. Lower-than-expected Benlysta sales are the primary cause of all this trouble. Without that approval, the company would likely have disappeared (or contracted beyond recognition). With it, the company is disappearing, and contracting anyway. . .

Comments (9) + TrackBacks (0) | Category: Business and Markets

You Should Take Chemistry: A Response

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Posted by Derek

The Washington Post has published another guest blog taking the opposite side of the recent "Why Are You Forcing My Son to Take Chemistry?" article.

S. Raj Govindarajan makes his case (some of which recapitulates points made by readers here). I doubt if he's convinced anyone who holds the view of the original authors, but I think he's on target with this part:

Should your son be forced to take chemistry? Absolutely. But the curriculum needs to be rethought in a way that would instill practical knowledge, curiosity about the world, and an appetite for at least understanding scientific achievement and its necessity/implications.

People don’t have to become scientists if they don’t want to, but they should have a fundamental understanding of scientific concepts. That way, people like myself need not be terrified that an ignorant public will vote to slash funding for scientific research and understanding. . .

Comments (9) + TrackBacks (0) | Category: Chemical News

The Generic Wellbutrin Problem: Whose Fault Is It?

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Posted by Derek

One of the questions I get asked most often, by people outside of the drug industry, is whether generic medications really are the same as the original branded ones. My answer has always been the same: that yes, they are. And that's still my answer, but I'll have to modify it a bit, because we're seeing an exception right now. Update: more exceptions are showing up in the comments section.

Unfortunately, "right now" turns out, in this case, to mean "over the last five years". The problem here is bupropion (brand name Wellbutrin), the well-known antidepressant. A generic version of it came on the market in 2006, and it went through the usual FDA review. For generic drugs, the big question is bioequivalence: do they deliver the same ingredient in the same way as the originally approved drug and formulation? The agency requires generic drug applications to show proof of this for their own version.

For bupropion/Wellbutrin, the case is complicated by the two approved doses, 150mg and 300mg. The higher dose is associated with a risk of seizures, which made the FDA grant a waiver for its testing - they extrapolated from the 150mg data instead. And right about here is where the red flags began to go up. The agency began to receive reports, almost immediately, of trouble with the 300mg generic dose. In many cases, these problems (lack of efficacy and/or increased side effects) resolved when patients switched back to the original branded formulation. That link also shows the pharamacokinetic data comparing the two 150mg dosages (branded and generic), which turned out to have some differences, mostly in the time it took to reach the maximum concentration (the generic came on a bit faster).

At the time, though, as that link shows, the FDA decided that because of the complicated clinical course of depression (and antidepressant therapy) that they couldn't blame the reported problems on a difference between the two 300mg products. A large number of patients were taking each one, and the number of problems reported could have been explained by the usual variations:

The FDA considers the generic form of bupropion XL 300 mg (Teva Pharmaceuticals) bioequivalent and therapeutically equivalent to (interchangeable with) Wellbutrin XL 300 mg. Although there are small differences in the pharmacokinetic profiles of these two formulations, they are not outside the established boundaries for equivalence nor are they different from other bupropion products known to be effective. The recurrent nature of (major depression) offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product. The adverse effects (e.g., headache, GI disorder, fatigue and anxiety) reported following a switch were relatively few in number and typical of adverse drug events reported in drug and placebo groups in most clinical trials. . .

But they seem to have changed their minds about this. It appears that reports continued to come in, and were associated most frequently with the generic version marketed by Teva (and produced by Impax Pharmaceuticals). That FDA page I've quoted above is not dated, but appears to come from late 2007 or so. As it turns out, the agency was at that time asking Teva to conduct that missing bioequivalence study with their 300mg product. See Q12 on this page:

FDA continued to review postmarketing reports throughout 2007. In November 2007, taking into consideration reports of lack of efficacy, FDA requested that Impax/Teva conduct a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The study protocol stipulated the enrollment of patients who reported problems after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg. Impax/Teva began the study, but terminated it in late 2011, reporting that despite efforts to enroll patients, Impax/Teva was unable to recruit a significant number of affected patients.

The agency apparently was continuing to receive reports of problems, because they ended up deciding to run their own study, which is an uncommon move. This got underway before Teva officially gave up on their study, which gives one the impression that the FDA did not expect anything useful from them by that point:

In 2010, because of the public health interest in obtaining bioequivalence data, FDA decided to sponsor a bioequivalence study comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The FDA-sponsored study enrolled 24 healthy adult volunteers and examined the rate and extent of absorption of the two drug products under fasting conditions. In that study, the results of which became available in August 2012, Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.

That FDA-sponsored study is what led to the recent decision to pull the Imapax/Teva 300mg product from the market. Their 150mg dosage is still approved, and doesn't seem to have been associated with any increased reports of trouble (despite the small-but-real PK differences noted above). And it's also worth noting that there are four other generic 300mg bupropion/Wellbutrin products out there, which do not seem to have caused problems.

How big a difference are we talking about here? There are several measurements that are used for measuring blood levels of a drug. You have Cmax, the maximum concentration that is seen at a given dosage, and there's also Tmax, the time at which that maximum concentration occurs. And if you plot blood levels versus time, y