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: Twitter: Dereklowe

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November 30, 2009

More Binding Site Weirdness

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Posted by Derek

Now here's an oddity: medicinal chemists are used to seeing the two enantiomers (mirror image compounds, for those outside the field) showing different activity. After all, proteins are chiral, and can recognize such things - in fact, it's a bit worrisome when the enantiomers don't show different profiles against a protein target.

There are a few cases known where the two enantiomers both show some kind of activity, but via different binding modes. But I've never seen a case like this, where this happens at the same time in the same binding pocket. The authors were studying inhibitors of a biosynthetic enzyme from Burkholderia, and seeing the usual sorts of things in their crystal structures - that is, only one enantiomer of a racemic mixture showing up in the enzyme. But suddenly of their analogs showed both enantiomers simultaneously, each binding to different parts of the active site.

Interestingly, when they obtained crystal structures of the two pure enantiomers, the R compound looks pretty much exactly as it does in the two-at-once structure, but the S compound flips around to another orientation, one that it couldn't have adopted in the presence of the R enantiomer. The S compound is tighter-binding in general, and calorimetry experiments showed a complicated profile as the concentration of the two compounds was changed. So this does appear to be a real effect, and not just some weirdo artifact of the crystallization conditions.

The authors point out that many other proteins have binding sites that are large enough to permit this sort of craziness (P450 enzymes are a likely candidate, and I'd add PPAR binding sites to the list, too). We still do an awful lot of in vitro testing using racemic mixtures, and this makes a person wonder how many times this behavior has been seen before and not understood. . .

Comments (4) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News | Drug Assays

November 28, 2009

Recommended Books For Medicinal Chemists, Part One

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Posted by Derek

I asked recently for suggestions on the best books on med-chem topics, and a lot of good ideas came in via the comments and e-mail. Going over the list, the most recommended seem to be the following:

For general medicinal chemistry, you have Bob Rydzewski's Real World Drug Discovery: A Chemist's Guide to Biotech and Pharmaceutical Research. Many votes also were cast for Camille Wermuth's The Practice of Medicinal Chemistry. For getting up to speed, several readers recommend Graham Patrick's An Introduction to Medicinal Chemistry. And an older text that has some fans is Richard Silverman's The Organic Chemistry of Drug Design and Drug Action.

Process chemistry is its own world with its own issues. Recommended texts here are Practical Process Research & Development by Neal Anderson and Process Development: Fine Chemicals from Grams to Kilograms by Stan Lee (no, not that Stan Lee) and Graham Robinson.

Case histories of successful past projects are found in Drugs: From Discovery to Approval by Rick Ng and also in Walter Sneader's Drug Discovery: A History.

Another book that focuses on a particular (important) area of drug discovery is Robert Copeland's Evaluation of Enzyme Inhibitors in Drug Discovery.

For chemists who want to brush up on their biology, readers recommend Terrence Kenakin's A Pharmacology Primer, Third Edition: Theory, Application and Methods and Molecular Biology in Medicinal Chemistry by Nogrady and Weaver.

Overall, one of the most highly recommended books across the board comes from the PK end of things: Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization by Kerns and Di. For getting up to speed in this area, there's Pharmacokinetics Made Easy by Donald Birkett.

In a related field, the standard desk reference for toxicology seems to be Casarett & Doull's Toxicology: The Basic Science of Poisons. Since all of us make a fair number of poisons (as we eventually discover), it's worth a look.

There's a first set - more recommendations will come in a following post (and feel free to nominate more worthy candidates if you have 'em).

Comments (21) + TrackBacks (0) | Category: Book Recommendations | Drug Development | Life in the Drug Labs | Pharmacokinetics | The Scientific Literature | Toxicology

November 25, 2009

Light Blogging

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Posted by Derek

I'll have the Grand Recommended Med-Chem Book List up later today, but otherwise, blogging will be light over the next few days, what with Thanksgiving and all. A very happy feast to my readers who are celebrating, and hey, those of you in other countries, feel free to enjoy yourselves, too!

Comments (2) + TrackBacks (0) | Category: Blog Housekeeping

November 24, 2009

Applied Organic Synthesis: Chocolate Pecan Pie

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Posted by Derek

I first published this recipe on the blog a couple of years ago, and I'd like to put it out there again for those readers who will be celebrating Thanksgiving this week. This is a slightly modified version of Craig Claiborne's recipe in the New York Times Cookbook
. He was a Southerner himself, so he knew his pecan pie. Substitutions for the ingredients are listed after the recipe:

Melt 2 squares (2 oz.) baking chocolate with 3 tablespoons (about 43g) butter in a microwave or double boiler. Combine 1 cup (240 mL) corn syrup and 3/4 cup sugar (150g) in a saucepan and bring to boil for 2 minutes, then mix the melted chocolate and butter into it. Meanwhile, in a large bowl, beat three eggs, then slowly add the chocolate mixture to them, stirring vigorously (you don't want to cook them with the hot chocolate goop).

Add one teaspoon (5 mL) of vanilla, and mix in about 1 1/2 cups of broken-up pecans, which I think should be about 150g. You can push that to nearly two cups and still get the whole mixture into a deep-dish pie shell, and I recommend going heavy on the nuts, since the pecan/goop ratio is one thing that distinguishes a home-made pie. Bake for about 45 minutes at 375 F (190C), and let cool completely before you attack it. Note that this product has an extremely high energy density - it's not shock-sensitive or anything, but make the slices fairly small.

Note for non-US readers: the baking chocolate can be replaced by 40 grams of cocoa powder (not Dutch-processed) and 28 grams of some sort of shortening (unsalted butter, vegetable shortening, oil, etc.) If you don't have corn syrup, then just use a total of 350g white sugar, and add 60 mL water to the recipe.

Comments (21) + TrackBacks (0) | Category: Blog Housekeeping

Fear Of Academic Chemistry?

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Posted by Derek

A comment to yesterday's post made a point that seemed instantly familiar, but it's one that my own thoughts had never quite put together. All of us who do medicinal chemistry came out of academic labs; that's where you get the degrees you need to have to be hired. Many of us worked on the synthesis of complex molecules for those degrees, since that's traditionally been a preferred base for drug companies to hire from. (You get a lot of experience of different kinds of reactions that way, have to deal with setbacks and adversity, and have to learn to think for yourself. Plus, if you can put up with some of the people who do natural products synthesis, the thinking goes, you can put up with anything).

Here's the interesting part, though. People who do the glass-filament spiderweb-sculpture work that is total natural product synthesis will defend it on many grounds (some more defensible than others, in my view). They have, naturally enough, a bias in favor of that kind of work. But have those of us who've done that kind of chemistry and then moved on to industry ended up with the opposite bias? Have we reacted against the forced-march experience of some of our early training by resolving never to get stuck in such a situation again (which is reasonable), but at the same time resolved never to get stuck doing fancy synthesis again?

That one may not be so reasonable. And I don't mean that we avoid twenty-step syntheses for irrational reasons, because there are perfectly rational reasons for fleeing from such things in industrial work. But this bias might extend further. Take a workhorse reaction like palladium-catalyzed coupling - that's just what people tend to think of when they think of uninspiring industrial organic synthesis, two or three lumpy heteroaromatics stuck together with Suzuki couplings, yawn. One of my colleagues, though, recently mentioned that he saw too many people sticking with rather primitive conditions for such reactions and taking their 50% yields (and cleanup problems) as just the normal course of events. And he's got a point, I'd say. There really are better conditions to use as your default Pd coupling mixture than the ones from the mid-1990s. You don't have to always clean all the red-brown gunk out from your product after using (dppf) as your phosphine ligand, and good ol' tetrakis is not always the reagent of choice. But a lot of people just take the standard brew, throw their starting materials in there, and bang 'em together. Crank up the microwave some more if it doesn't work.

I can see how this happens. After all, the big point that people have to learn when they join a drug research effort is that chemistry is not an end in itself - it's a tool to make compounds for another end entirely. If you're just making analogs in the early stages of a new project, no one's going to care much if your yields are low, because the key thing is that you made the compounds. I've said myself (many times) that there are two yield in medicinal chemistry: enough, and not enough. Often, perhaps a little too often, five milligrams qualifies as "enough", which means that you can check off a box through some really brutal chemistry.

But at the same time, if you could make simple changes to your reaction conditions, or to the kinds of reactions you tend to run, you could potentially make more compounds (because you're not spending so much time cleaning them up), make them in higher yields (or make your limited amount of starting material stretch further), or make more interesting (and patentable) ones, too. I think that too many of us do tend to get stuck in synthetic ruts of various sorts.

Perhaps the main cause of this is the pressure of normal drug discovery work. But I do have to wonder if some of the problem is a bit of aversion to the latest, hottest reagent or technique coming out of the academic labs. To be sure, a lot of that stuff isn't so useful out here in what it pleases us to call the real world. But there are a lot of things we could stand to learn, as well. Palladium couplings used to be considered kind of out-there, too, you know. . .

Comments (30) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs

November 23, 2009

K. C. Nicolaou, Call Your Office

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Posted by Derek

While I'm putting up odd chemical structures today, I thought I'd add this one, Alasmontamine A, from the latest Organic Letters preprint stream. Natural products scare me:
Anyone who wants to take a crack at this one synthetically, you just go right ahead without me. It is pretty much a dimer, though, so it's only about half as awful as it looks. Which is still enough. It doesn't seem to have much biological activity, but if you can sell it as something to do with green chemistry, nanotech, or alternative energy, you should be able to round up some money, right?

Comments (39) + TrackBacks (0) | Category: Chemical News

Ozonides As Drugs: What Will They Think of Next?

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Posted by Derek

You know, I often think that I have too narrow a view of what kinds of structures can go into drug molecules. (That may come as worrisome statement for some past and present colleagues of mine, who feel that my tolerances are already set a bit too wide!) But I do have limits; there are some structures that I just wouldn't make on purpose, and which I wouldn't submit for testing even if I made them by accident.

Surely ozonides fall into this category. But when I put the "Things I Won't Work With" stamp on them, at least as far as making them on scale and actually isolating them, some readers pointed out that people were investigating them for antimalarial activity. And here we are, with a new paper in J. Med. Chem. on their activity and properties.

Arterolane is the lead compound, which is in Phase III trials as a combination therapy. And it has to be one of the funkier structures ever to make it as far as Phase III, for sure, with both an ozonide and an adamantane in it. Those two, in fact, sort of cancel each other out - the steric hindrance of the adamantane is surely one of the things that makes the ozonide decide not to explode, as its smaller and more footloose chemical relatives would. You get blood levels of the stuff after oral dosing, a useful (although not especially long) half-life, and no show-stopping toxicity.
Endoperoxides are already known as antimalarials, thanks to the natural product arteminisin, which has led to two synthetic derivatives used as antimalarials. So the step to ozonides was, structurally, a small one, but must have been rather larger psychologically. And that's definitely not something to discount. I probably wouldn't have made compounds of this sort, and it's unnerving (even to me) that arterolane has gone further into the clinic than anything I've ever made. I have to congratulate the people who had the imagination to pursue these things.

Comments (18) + TrackBacks (0) | Category: Drug Development | Infectious Diseases | Odd Elements in Drugs

November 20, 2009

But These Reagents, Where Are They?

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Posted by Derek

I'm home today (sick children, etc.), so I'm blogging from next to my daughter's guinea pig cage rather across the hall from my lab. But I have a lab-based question to throw out: what would you say is the chemistry technique or reagent with the worst publication-to-real use ratio?

I have a couple of nominees to get things rolling. For reagent, I would like to advance the montmorillonite clay stuff. I cannot count how many papers I have seen on its use as a Lewis acid, catalyst, and all-around good thing to have, but I have never used it myself, never spoken with anyone who has, and never (to my recollection) heard it suggested as a possible thing to try when someone encountered a synthetic problem. For all I know it's a fine reagent, but its footprint does not seem to be very large. I actually have used benzotriazole, but I've never seen an actual container of montmorillonite K-10.

For general technique, I'm tempted to nominate ionic liquids. Man, are there ever a lot of publications on those things, but again, I've never actually encountered them in actual practice. I have heard second-hand of people trying them, so I guess that counts for something, but it still seems to be disproportionate compared to the avalanche of literature citations for the things. The craze seems to have peaked, but still not a week goes by that I don't see a paper.

Nominations? As with the book recommendation post, I'll assemble things into master lists.

Comments (49) + TrackBacks (0) | Category: Life in the Drug Labs

Merck, Shopping in the UK?

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Posted by Derek

So, according to this report, Merck is scouting out locations for a UK facility. No word if it's supposed to have a research component, but. . .as a correspondent points out, if only there were a large research campus that they could somehow get their hands on, convenient to both Cambridge and London, with all the facilities they might need. . .hmmm. . .

Comments (22) + TrackBacks (0) | Category: Business and Markets

November 19, 2009

What Are the Best Med-Chem Books?

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Posted by Derek

I get regular requests to recommend books on various aspects of medicinal chemistry and drug development. And while I have a few things on my list, I'm sure that I'm missing many more. So I wanted to throw this out to the readership: what do you think are the best places to turn? This way I can be more sure of pointing people in the right directions.

I'm interested in hearing about things in several categories - best introductions and overviews of the field (for people just starting out), as well as the best one-stop references for specific aspects of drug discovery (PK, toxicology, formulations, prodrugs, animal models, patent issues, etc.)

Feel free to add your suggestions in the comments, or e-mail them to me. I'll assemble the highest-recommended volumes into a master list and post that. Just in time for the holidays, y'know. . .

Comments (35) + TrackBacks (0) | Category: Life in the Drug Labs | Pharma 101

Plavix vs. Effient

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Posted by Derek

The InVivo Blog has a good article on a controversy in the blood-thinning market. Plavix (clopidogrel) has a very strong share of that, of course, but since Effient (prasugrel) was finally approved, Lilly and Dai-Ichii are looking to take as much of that market as they can. And one opening might be that not everyone responds similarly to Plavix.

In some cases, that's because there are some drug-drug interactions, a problem the FDA has recently addressed. The proton pump inhibitors, especially, are metabolized through the CYP2C19 pathway. That's a problem, since that enzyme is needed to convert clopidogrel into its active form (Plavix, as it comes out of the pill, is a prodrug - its thiophene ring needs to get torn open). This sort of thing has been seen many times before - it's one of the many headaches that you can endure in drug development as you profile the metabolizing pathways for your drug candidate and compare them to the other compounds your patient population might be taking. There are some combinations that just will not work (several involving CYP3A4, which is often the first one you test for), and it looks like we can add Plavix/2C19 to the list.

But the population genetics of the 2C19 enzyme are rather heterogeneous. About a third of the patients taking Plavix have a less-active form of the enzyme to start with, and they might not respond as robustly to the drug. The FDA has emphasized this effect in its latest public health warning. That's an opportunity for Effient, since it doesn't go through that metabolic route.

The In Vivo people point out, though, that this story isn't being driven by the usual players. It's not the FDA that's pushed to find this out, and it's not even Eli Lilly. It's Medco and Aetna. They studied their insurance claims data to see if the numbers supported the proton pump inhibitor/Plavix interaction, found that they did, and publicized their findings - and that led to an actual observational trial from BMS and Sanofi, which confirmed the problem. Now Medco is going further, and is actually running its own observational study comparing Plavix and Effient. Their theory is that the efficacy that Lilly showed compared to Plavix was driven by the (deliberate, one assumes) inclusion of a high number of poor metabolizers.

Medco is getting ready for generic Plavix, and trying to keep its costs down by making the case that the drug will do the job just fine for most patients. They could, on the other hand, end up making the case for Effient in that poor-metabolizing third of the patients, which would also be interesting. Lilly would presumably settle for that, although they'd like even more of the market if they can get it, naturally.

And I have to say: I like this sort of thing. I like it a lot. This, to me, is how the system should work. Companies are pursuing their own competing interests, but in the end, we get a higher standard of care by finding out which drug really works for which patients. The motivation to do all this? Money, of course, earning it and saving it. This may sound crass, but I think that's a reliable, proven method to motivate people and companies, one that works even better than depending on their best impulses. You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people. Worth a try.

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