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Derek Lowe The 2002 Model

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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 25, 2007

You Do The Easy Stuff; I'll Do the Easier

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Posted by Derek

A reader from inside the industry writes:

How is 'what's made' influenced by the synthetic knowledge of the individual med chemist? I would guess that with all the pressure on targets that you've written about, there must be some level of sub-conscious selection based on ease of synthesis, so the difficult structures either never get made or get made later. . .(but) difficulty is a subjective term. The better the chemist the more molecules fall into the easy category. . .

. . .One thing I've noticed is the explosion in bi-aryls since the Suzuki and related chemistry came along. Is this due to a sudden realsiation that bi-aryls could be good molecules or is it due to the fact that Suzuki chemistry is easy?

I've wondered about this one myself, as have many other chemists I've known. It's true that as synthetic chemists we tend to go for the low-hanging fruit; I don't think that anyone could deny it. And that's largely due to pressure to produce results, although I wouldn't rule out laziness, either (never rule out laziness).

But you can often get pretty interesting things to happen by doing simple reactions and small changes. Think about the number of times you've seen activities totally altered by one methyl group, or the metabolic problems that have been fixed by adding a para-fluoro. We don't feel as much need to move into new territory as we might.

As for variation between individual chemists, that's why you want to hire a set of people with diverse backgrounds. (And no, I don't mean HR-style diversity, I mean chemical and scientific diversity). The literature is big enough and varied enough so that people can have a lot of experience and still not overlap with their colleagues much in their favorite reactions and structures. People will still go for the easy stuff, but with any luck there will be enough different definitions of "easy stuff" to keep people from piling up too much.

But I think that this factor isn't quite as big as it used to be, what with the advent of modern literature searching. People can pull out all sorts of reactions from the literature and give 'em a try - it's hard to remember that it used to be quite a bit harder to do that. So what do my industrial readers think - do we just make the easy stuff? If we do, is that a problem? How much is "easy" a function of who's doing the chemistry? And has that changed over time?

Comments (12) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs


1. rk on November 25, 2007 10:21 PM writes...

With the pressure placed on medicinal chemists these days I have seen many colleagues make molecules because they can easily be made rather than making the molecules that should be made i.e. the ones that answer the questions.

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2. processchemist on November 26, 2007 4:58 AM writes...

I'm seeing quite a lot of "not easy at all" targets moving from medchem to tox batches.
And often chemistry easy on the paper is impossibile or really difficult in the real world (and I think mostly about suzuki reactions).

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3. LNT on November 26, 2007 11:39 AM writes...

I think one underappreciated innovation that has changed the playing field is the advent of mass-directed HPLC. It really allows a "not so easy at all" reaction to give a usable product. I don't think twice when I do a 100 mg reaction, throw it on the HPLC, and isolate 15 mg of product to submit for testing. The reaction may be a 3-component reaction using a starting material that is only 70% pure. But hey, I was able to get usable product out of the other side -- so who care?

Unfortunately, it's probably the process chemists that pay the price for mindsets like mine.

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4. CMC guy on November 26, 2007 12:27 PM writes...

For most part current mentality is to make easy stuff which can be a problem if creates unwillingness to stretch to achieve demand of target. Probably gotten worse over time.

Chemists can be guilty of following fads in new (or likely rediscovered) reactions and often will see a popular transformation get applied in most every project (Total synthesis papers in the 80s full of many uses of Mitsunobu). Perhaps a stimulating seminar, well written paper or publication of straightforward procedure spawns simultaneous interest at several companies. Derek you are correct as access and searching tools are so much better than 10-15 year ago and now some good resource books (Larock) but most people see the same things (although if read Russian probably still may be some buried gems).

Likewise, there in tendency to gravitate to things known so repeatedly implement reactions learned in Grad school or old projects, which have become easy to because they are familiar, or already worked through subtleties necessary that are not in literature. As was recently blogged about if you are judged on quantity not quality you will bang out 4-5 easy compounds using what you are comfortable with rather than attempt to go after the supposedly best molecule that is difficult or foreign to make. Building a critical mass that provides diverse knowledge base can overcome some of the activation energy although still need at atmosphere where do not get penalized for tackling harder choice that did turned into sour fruit.

Combinatorial chemistry was accused of only making easy stuff, which was/is partly true, however does allow potential to combine aspects in unique ways that may not try otherwise.

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5. milkshake on November 26, 2007 1:58 PM writes...

Biaryls are metabolically stable and conformationally restricted. Its a good piece of scaffold - and with a wide selection of boronic acids and mild reaction conditions that tolerate lots of functional group, it is a powerfull way of building molecules.
And its not too finnicky - even if the yield is not always great you can be pretty sure that you get some product in 9 out of 10 cases.

Mitsunobu has some of the same good properties.

When choosing what chemistry to try first, you want something that needs as little react condition development as possible.

Also, people have different preferences based on their experience (or lack of it). I once missed a very simple and powerful solution of how to make an isoster of our active but insoluble lead - I got this idea but then checked the literature and realised the cyclization would prove a wrong (and inactive) regioisomer.
Which was perfectly true - so I did not do it. But a colleague did it anyway, isolated the 10% of the regioisomer from the mixture (they were very apart on silica) and it was a great compound. Later we even found out one can reverse the cyclisation regioisomer ratio from 1:10 to 4:1 by changing the conditions.

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6. Green Koala on November 26, 2007 2:54 PM writes...

I don't think a med chemist's personal experience plays a majority of the role in what he/she makes. Most of us enjoy the challenge of doing new/different chemistries, and after a few years, who wouldn't want to avoid making sulfonamides, amides, biaryls, and the like.

Doesn't mean that novelty can't come from some relatively simple chemistry, and some of the most elegant work I've seen has been with some simple chemistry. We all usually consider what the best compounds to test an idea or ideas with are, then figure out how to make them. The majority of the time it at least partially gets us into unknown territory synthetically.

I have had a couple of individuals who tended to focus too much in one area of synthesis (methyl/ethylbromoacetate on any and every core followed by hydrolysis/amide formation, for example); but, that is why there are project leaders now, isn't it.

I do agree with Derek in that it is by far most helpful to have a diversity in experiences around you; and it helps to move around in different target classes and therapeutic areas to do this if you have to.

But to the original question, I don't think it plays a big role, but it can be beneficial - who wouldn't want to instill some novelty using an obscure [3+2] cyclization they did back in grad school?


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7. Jose on November 26, 2007 3:55 PM writes...

CMC guy- I, too, wonder how many buried treasures there are to be found in the old Soviet literature. Anyone have an estimate of how much of that has been been abstracted, let alone translated?

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8. Off D. Topic on November 26, 2007 4:17 PM writes...

Anyone notice that Atom Pusher's blog went dark today? Google cached the last post:

Sunday, November 25, 2007
The light at the end of the tunnel...

-- someone please tell me that it's not a train. Or so goes the song by Cracker.

Our little operation is now taking the steps necessary to go public. Sometime in the future, the management will be doing the road show and all of that good stuff. Here's the important disclaimer: even though I haven't disclosed the name of my company some people might consider this an insider tip. Well don't! I don't know anything about the company that isn't already disclosed to the public. I'm not that important. The timeline, pipeline, future projects and company status are out there for public evaluation. Beyond that I have no comment as to when we go public or what our future projects are: etc. etc.

I worry somewhat that this is the beginning of an exit strategy for the CEO. I hope he isn't leaving us to be devoured by general Franco and his cronies. I also worry what happens after we go public. Do we become a target for a Pfizer slash and burn? Then again I have to wonder if milkshake is right. Is a layoff sometimes the best thing that could happen to you? In terms of employability, I'm much better off than most of my coworkers. It is deeply frustrating how crappy scientists get hired simply because they know the right people. Time to practice my sucking up, but only on the right-people-types.

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9. milkshake on November 26, 2007 4:20 PM writes...

Old soviet literature is not worth much. It is like the western articles before 1955. The trouble is that until 90s they did not have that many decent NMR instruments in Russia so lots of stuff published is not reliable - I isolated a mix of isomers couple times that was described in the russian lit as pure compounds.(Then it become clear why nobody in West realy referenced the work in question). Also there is lots of organophosphorus and fluorine stuff, it looks like military application to me but not of much general interest.

The other trouble is that the articles are often very short but quite convoluted - it is not much fun to read it.

I don't want to knock it down entirely (India-published journals are worse) - and there were few excellent russian steroid total synth papers in 50s. But it is quite general phenomenon that science does not prosper in totalitarian regimes, even if the funding adequate.

I would rather like to see the numerous review articles that get published in Japanes-only journals.

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10. dorf on November 26, 2007 9:32 PM writes...

Think software: code builds and voila more code and then Windows

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11. eugene on November 27, 2007 1:41 AM writes...

milkshake, once again I have to disagree with that broad statement. Seeing as my subfield, which is certainly worth a lot now, is based on Russian chemistry from the 70s published in Russian journals. Guess what all the JACS and Angewandte articles that come out cite in the first few references?

Your experience is that of one person; it is inadequate to characterize all of Soviet literature fairly. Maybe all of the Kazakh chemical literature though. There are lots of excellent Russian synthetic chemists who did great stuff, and still do great stuff (in the US now). Their science prospered very well in the totalitarian regime to my (and my competitors/colleagues') current benefit.

China seems to be doing pretty well right now so the totalitarian - scientific prosperity analogy doesn't hold water.

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12. CMC guy on November 27, 2007 11:11 AM writes...

In terms of Russian literature I only have Antidotal Evidence but my old boss in grad school and then later encountered a couple colleages in industry would occasionally pull out some obscure cite from a Russian Journal as precedent to do a reaction. Often procedures (or translation thereof) were thin and had fair bit of adjustments involved but usually a good start.

Over the years I have repeated a number of compounds from pre-NMR literature (usually for starting mats) and have actually been amazed how the chemists were able to do synthesis without our modern tools. Most were from German or UK authors pre-WWII with oldest around 1904 and lead to expected products.

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