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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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November 24, 2009

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


COMMENTS

1. Deep Lurker on November 24, 2009 10:05 AM writes...

In my own experience, a big sticking point for using "hot new chemistry" is the need to make the hot new reagents. If/once the reagents are available from Aldrich, I'm much more willing to try the chemistry.

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2. anon on November 24, 2009 10:19 AM writes...

Lurker, some might argue that you are the poster child for what is wrong with the industry. The mere fact that you simply want to take the easy way out and buy something, instead of making it, should not be enough to keep someone from using a potentially useful tool. This is the general mentality of industry: here and now. If I have to make it, it is not worth it time wise. Well, no wonder 20 years later it is the same story: get lead compound, make derivatives, test, and repeat. Sure it worked for the "low lying fruits." Now, when the industry has to make the transition to the more difficult targets, there is so much resistance from industry that is literally crippling it. And maybe one reaction is to disregard the new "hot" topics that may actually be very medically relevant (RNAi was a "hot" topic too).

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3. a-non on November 24, 2009 10:29 AM writes...

isn't this why it is important for companies to continually hire new people - so that they bring with them new ideas and techniques. Also, I had thought why ppl with PhD degrees where desirable as they have been taught/could already/have learned to think for themselves (as Derek pointed out)

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4. opsomath on November 24, 2009 10:34 AM writes...

There's nothing wrong with the attitude of "I will not use this shiny new technique until the reagents to perform it are commercially available." Or at least, the procedure to make the reagents are easy with commercially available precursors. Otherwise, you can spend all your time trying to repeat a fancy new technique which turns out to be unreliable - and which offers little benefit for you, because it's not original.

Even in an academic lab, I spend a lot of my time thinking "How can I get to my target compounds as quickly as possible in adequate yield for the experiments I want to do?" Not "How can I make my target compounds in the most elegant and efficient way?" As Lowe's Laws of the Lab say - think twice before getting rid of the old route, or else you will spend months saving time.

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5. David P on November 24, 2009 10:40 AM writes...

A lot of those fancy new reagents need to be make before you can try it. So that is a barrier, especially when there is no guarantee that the fancy reagent will be any better. But a further impediment is that the fancy reagents also often need fancy set-ups that are just not available to the average work-horse of the drug discovery lab. Academic labs have them because they are the priomary focus of their work, but an industrial lab might need it once in a blue moon - not justifiable. Even potentially useful equipment like microwaves or H-Cubes get looked at carefully by people in charge of the capital budgets. Where I worked before, we had a lot of shared Companions, never mind fancy stuff.

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6. imarx on November 24, 2009 10:41 AM writes...

anon, the problem with making new reagents/ligand systems is you never know if they will work with your particular system. If the standard one-size-fits-all stuff doesn't work too well, you already know your substrate is pretty finicky and there's a good chance most of the new stuff won't work either. How much time do you spend making new ligands to test on your system, especially when there are other things you could be making? A month? Two months? Easier for grad students working on a natural product to justify than medicinal chemists. Also, many times making these new ligands requires anhydrous/dry-box techniques which industry labs aren't really equipped for. When you work in industry for a while you learn not to place too much importance on any one particular compound (unless you have a really good reason for doing so), as the odds are pretty low that the compound you are trying to make is THE ONE.

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7. Biobrit on November 24, 2009 11:36 AM writes...

@anon et al. I kinda agree - its not that we don't want to spend the time making the reagents, its just a healthy appreciation that by the time we have, we've probably moved on to a different area anyway. What was hot last week, is not as a new set of SAR came out and we've moved on. Much as it would be great to spend time optimizing both catalysts, then also conditions, but generally the bog standard, just enough yield gets you enough answers fast enough to see if it warrants more exploration.

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8. Biobrit on November 24, 2009 11:47 AM writes...

@Derek - this is a little off topic, but perhaps related.

"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."

I wonder about the communities opinion if in fact the industry tends to be too narrow minded in this regards. Where I have worked has tried to bring good people in from a broad cross section of backgrounds, all organic chemistry, but not all natural products synthesis. But I have heard of labs that only want Nicolaou and Lay people, for example. To my mind, this isn't good for creativity as everyone thinks more alike, but thats only MHO.

I vividly remember talking to some reps from one of the big pharmas visiting my graduate school, just before I started a postdoc with a very reputable prof. "Why don't WE tell you who to do your postdoc with" was their advice. Of course, I never took it, and managed to do pretty well in the industry despite them.

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9. You're Pfizered on November 24, 2009 11:53 AM writes...

A fair amount of the newer metal-based chemistry typically involves an industrial chemist's two most dreaded words: Glove box. I don't know about where many of you work, but there are none here. I tend to skip over those reagents/reactions pretty quickly.

Most medicinal chemists are willing to suffer poor yields with hellish purification to get a compound or two into the testing queue, where, more often than not, it will die. Spending an extra week optimizing the chemistry to made those compounds is potentially wasted time.

If that compound does show interesting activity, then you can spend the time and energy improving the syntheses. Hard to justify doing it before hand when it may simply end there.

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10. milkshake on November 24, 2009 1:04 PM writes...

Chemistry is an end in itself - It is a religion and we are a part of the same congregation (the First Church of Synthetic Organic Chemistry). We speak among ourselves in the jargon and we hold the communion with the same chemicals.

And there are heretics and the dogma-enforcers, schism-makers, the lukewarm ones and the fanatics, the cliques and secret orders - up to an occasional albino monk. Making the drug candidates is the stated purpose but in actuality our mission has more to do with the world domination

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11. CRH on November 24, 2009 1:08 PM writes...

To #2:

If 100% of what was published actually worked; then I would say you have a point. But, what percentage of reactions in the literature actually work as presented, AND in a very general manner? I'd say ~15-25%, no more. So, you are already expecting a 75+% chance of failure, PLUS you have to take time to (maybe) make the intermediates, catalysts, etc.? No thanks. No offense to most of the methodology out there coming from any lab (academic or industrial), usually the "hot item" needs a little smoldering before it's ready for the masses.

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12. Anonymous on November 24, 2009 1:52 PM writes...

I worked on reliable and extendible academic syntheses, and tested awful ones. Poorest performers of all, carbohydrate chemistry papers- if you think that no one is performing carbohydrate chemistry in industry, I have a single word: fondaparinux (about complex multistep processes).
Some fresh air sometimes hits also the structures coming from industry: in a landscape of aryls fused and coupled, saxagliptin and other cyanoproline based DPP4-inhibitors bring something different. I also remember extended SAR studies on epothilones and the spectacular fiasco of discodermolide (that has something to do with the loss of popularity of NPs in industry, I think).
Ah, and if flu pandemia will get really serious, maybe some second line antiviral will be of use and people will have some fun with shikimic acid and NANA derivatives (some already obtained some results with other neuraminidase inhibitors - peramivir - not exactly simple).

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13. processchemist on November 24, 2009 1:54 PM writes...

I forgot to sign last message, sorry

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14. Mithrandir on November 24, 2009 3:43 PM writes...

The tendency to stick to simple stuff to the exclusion of better if fancier stuff exists outside of chemistry as well (like, say, in software, which is my field). I suspect it's a combination of swearing off complex work when you leave academia, and the need in industry to make sure that lowest common denominator colleague of yours can still understand what's going on.

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15. CMCguy on November 24, 2009 3:53 PM writes...

There are two longstanding debates I see in this Post. One involves Mission Focus where academic labs are (hopefully?) there to provide education while Industry is tasked with generating products (and to some MBAs profit is only product). It can be indeed an effective learning experience to chase a complex Natural Product where time-frames, burn-rate and results (publications & renewed funding) have different demands. As well noted the typically gained board exposure to variety of chemistry, perseverance and mental activation is good. Often such background only is partial training for Industry where working in a Team, particularly multidisciplinary ones, and the project pressures/constraints are more dominate in daily activity. So unless said molecule has great potential as a medicine plus means to produce in scale potential it does not fit with common Industry objectives where time is money.

The other avenue of discussion is where the best medchemists come from and here can get into ties with "Bigname lab/institution". This has been established policy in Pharma, some places even overtly so, that could recruit "the cream of the crop" which means overabundance of certain groups. While there may be a few advantages to "better pedigree" it can be artificial in the long run where each person needs to stand on own capabilities. I have seen many with "underprivileged" backgrounds excel over those "prime draft choices" (and typically latter fall into kind mentioned in first paragraph).

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16. You're Pfizered on November 24, 2009 4:13 PM writes...

CMC-

The interesting thing in pharma today is that for an industry that is/was so pedigree conscious, even for MS level scientists, many are now more than happy to hand much of their chemistry to CROs where most of the folks are either from second/third rate schools, or have no college whatsoever.

That's where the real irony is for me.

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17. CMCguy on November 24, 2009 6:15 PM writes...

You're Pfizered 'tis true yet to me is a reflection of another topic with Good Science no longer a core of most Pharma's so the quality and potential of work done is much less a concern than the price or ability to acquire. "MBA-types" only look at the bottom-line and as long as they do not project where it likely to take company in the future the immediate benefit of outsourcing overseas is hard to refute.

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18. UK Chemist on November 25, 2009 3:11 AM writes...

I wonder if part of the reason is that many chemists,once in indusry,don't have time or can't be bothered to read the current chemical literature.

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19. cliffintokyo on November 25, 2009 4:31 AM writes...

#10
I endorse the gospel according to *Milkshake*, but I doubt that it will land a job for *Pfizered*....in the pharma industry anyway.
Let's not get too smug about our superiority; there are many PhD chemists who do good pharma R & D in China and India and some outclass their Western counteparts.... inevitable perhaps, as there are probably 10 times as many of *them*. Big pharma might want to think a bit more carefully about the implications for IP though... (CEO, you are thinking about that, are you not?)
Don't imagine for a second that anyone will be content to just make the compounds we designed...
they are *only* chemists afer all!

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20. processchemist on November 25, 2009 4:49 AM writes...

@19

For sure there is plenty of excellent indian and chinese scientists (these times no one talks about excellent russian or east european scientists, I wonder why). But there are not so much drugs (approved or in advanced clinical development) coming from chinese companies, or originated by chinese biotechs, so we're still waiting for the proof of concept of the current model.

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21. Little Miss Process on November 25, 2009 5:07 AM writes...

I think we see less avoidance of Hot New Stuff in process development - after all, it's part of our job to investigate as many different chemistries as possible in order to find the best/quickest/most convenient/whatever the managers want this month route, but I do still see people shying away from it - partly because of "oh, it won't work on plant" prejudice.

For medicinal chemists, there is a lot be gained by making network contacts with a process chemist or two - sometimes they've got the inside scoop on what Hot New stuff works, and what doesn't. (For example: My go-to Pd catalyst is now PEPPSI rather than tetrakis. It's a bit munchy, I've seen it eat coupling partners rather than couple them, but oh-my, it's active... And it keeps.)

People have also been discussing the value of a BigName/Institution background - we see the need for diversity here too - you can be a fab chemist on the bench (and on paper too), but that's bog-all use if you've got no common sense or aptitude for engineering. And I'm not really sure you can pick up common sense anywhere - either you have it, or you don't.

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22. You're Pfizered on November 25, 2009 9:15 AM writes...

21-LMC

I agree with you on this one. I know quite a few process chemists and we have one come to our regular chemistry group meetings. It's great to get their perspective on things because their heads aren't cluttered with biological ramblings and SAR trends. They see our issues as pure chemistry and that is a very useful set of eyes to have looking at your stuff.

18-Any chemist that isn't smart enough to use simple techniques (RSS, EMAIL alerts) to get useful information on current topics in organic chemistry probably deserves to get outsourced at some point. Going to the occasional seminar can sometimes bear fruit, but that's more hit-and-miss, IMHO.

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23. CMCguy on November 25, 2009 10:47 AM writes...

#21 LMP- I also agree interactions between med & process chemists is always good and it works both ways as often the medchemists can point out difficulties or experiments already attempted so process people can spend efforts more wisely.

In terms of Hot New Stuff being more applied in process I am not so sure as guess it depends on several factors. If one has to take 5-10 steps to make a fancy catalyst for one step is there value? Likewise if established conditions are "extreme" or undesirable solvents involved it can take a significant effort to transition for scale-up. I do think process chemist should always be open to new stuff but again have to discern how mush effort would be involved in actual integration. I think that takes the common sense you mention.

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24. BBooooooya on November 25, 2009 11:09 AM writes...

" "MBA-types" only look at the bottom-line and as long as they do not project where it likely to take company in the future the immediate benefit of outsourcing overseas is hard to refute."

of course, EPS, both this quarter and in the future is all that matters. No one is going to pay you to carry out nice fanciful work that can never be monetized. To be clear, companies like PFE have done a lousy job of ensuring future EPS by cutting the wrong places, and the market cap shows this.

In terms of outsourcing, this makes sense short and long term, at least for the drudge work that is most of chemistry/screening. it doesn't take a PhD from Harvard to mix reagents and stir, a well trained monkey (or robot) can do the same, and do it much more cheaply. Ditto mixing buffers and running gels.

There's a reason the NSF cites that 40+% of grad students at US schools are foreigners---Americans are realizing that these advanced degrees (for 75% of thos who obtain them) no longer add much value to the economy overall.

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25. David P on November 25, 2009 11:18 AM writes...

18: Yes I wonder how many do manage to keep up with literature over the long haul. Myself, I would have fits and starts until, like 22 says, I made use of email alerts. Much easier to keep up when you get an email reminding you to check out the latest Bio Med Chem Letters or see the new articles in J Med Chem.

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26. cliffintokyo on November 25, 2009 7:54 PM writes...

@20
Just wait a few years; I predict that *Pfizered* will soon seem like a friendly 'so long' gesture. As you rightly pointed out, biotech R & D in China is steadily building into a formidable force to be reckoned with.
But global pharma does need to convince the rapidly developing countries about the sanctity of our IP and the crucial importance of a robust patent system.
On the other hand: 'all's fair in love and war'. (Business competition is of course just a surrogate for physical conflict)
We can hardly complain, given the questionable morality of big pharma behaviour in recent years, if the business ethics of others is not all that we would wish; the hypocrisy of 'do as I say, not as I do' comes back to bit us in the end....in this instance, the research end.

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27. cliffintokyo on November 25, 2009 8:02 PM writes...

@26
PS: This story is becoming uncomfortably similar to 'who moved my cheese?'

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28. okemist on November 30, 2009 10:53 AM writes...

As a person who takes chemistry through phaseI and II, I typically see as the demand increases for new reagents the competition for suppliers increase and costs can go from > $1K per gram to dollars per gram in a year or two. Also glovebox techniques can be transferred to the plant; we typically use BuLi and LAH safely. So don't let new scare you, go be creative, and consult your friendly local neighborhood scale-up chemist to work it out if you are successful.

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29. galchem on November 30, 2009 4:26 PM writes...

I've been in big pharma for 20 years and I agree with many of the posts that while new, trendy techniques and reagents are fine and dandy for academic labs, they're not always feasible for industry labs. (Let's not even discuss combinatorial chemistry!). I don't think we industry types are not open to the new synthetic reagents coming out of academic labs. But given the intense pressure to produce more compounds, faster, often it doesn't make sense to invest valuable time in investigating new reactions/reagents to possibly make a few compounds. You can always come back later if the compound/series is hot. What chemist worth his rotovap is afraid of using a glove box??

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30. J-bone on December 5, 2009 3:22 PM writes...

With regard to the Big Name school issue, I find this trend very upsetting. I had lunch with a senior chemist at Thermo a year ago and he told me when he worked at Merck in Boston that his boss refused to hire anyone that wasn't from Harvard because that's where he went. Big part of the reason I hate schools like USC is the whole "pay a lotta money to go to school here and someday a Trojan is gonna take very good care of you" BS.

I didn't study chemistry as an undergrad, but switched to synthetic methodology for my grad. Got into a low/mid-tier school because the "good" ones wouldn't accept me based on my limited chemistry background. I did struggle initially, but made the most of my situation and became one of the more respected senior grads in our dept.

Just started a new postdoc doing med chem at a good quality institute, but looked for over a year to get one (even applied to this institute multiple times to multiple PI's). Economy is understandably a factor, but I can't help but wonder how many people threw my resume into the trash when they saw my school.

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