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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: Twitter: Dereklowe

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In the Pipeline

« How You Doin'? How's Everybody Doin'? | Main | And Speaking of Discovering Things. . . »

November 15, 2007

Maybe Not Improved, But Definitely New

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Posted by Derek

My lab and I have plans to start experimenting with several compound classes that we’ve never handled before. In fact, for some of these, no one’s handled them before. Some of these are not only novel as in patentable, for which fairly small changes can suffice, but novel as in what-the-heck-is-that. I couldn’t be happier.

Honestly, I have no idea of what I’d do with a job where I knew what was going to happen next. Years of science have ruined me for a lot of other occupations. I was putting some of these up on the board the other day, and mentioning what I’d like to try. “Do you know if you can do that?” someone asked, and I answered that no, I didn’t, and as far as I could tell, no one else did, either. I can draw out a bunch of reasonable-looking reactions, but the structures themselves may well have other ideas.

The first time I realized that I was in new territory, although to a much lesser degree, was back in my first year of graduate school. My first few reactions generated things that were already known in the group, naturally, and then I made some model systems that were already known in the literature. But pretty soon I remember making a compound that I realized just flat-out wasn’t in Chemical Abstracts, because no one had ever had the need to make it before. (As far as I know, no one’s had any need to make the stuff again, either – if someone has, I hope they got more use out of it than I did!) But there it was, in a flask: something that had never existed before.

My list of such compounds is now rather lengthy. In the drug industry, naturally, we spend just about all our time making compounds that haven’t existed before. (If they’ve been exemplified somewhere, you can forget about a patent on the chemical matter itself). Our livelihoods depend on cranking out thousands upon thousands of compounds that no one else has made. I haven’t seen the figures, but I’d guess that a large fraction of the new small organic molecules that get registered every year in Chemical Abstracts are from pharma. Those patents with the three-hundred-page experimental sections do start to add up.

This latest stuff, though, goes a few steps beyond that, to whole compound classes that no one’s touched yet. I may well find that there’s a whole set of very solid reasons why these things haven’t appeared in the literature – perhaps these reasonable reactions of mine have been tried in recent years, but found only to produce more of that gooey dark stuff in the bottom of the flask. We shall see. I’ve certainly made my share of that material.

But I doubt that all of them are in that category. So with any luck, soon I’ll be making something no one’s ever made, and finding things out about it that no one’s ever discovered. And as I said, I couldn’t be happier about that.

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs | Who Discovers and Why


1. molecular architect on November 15, 2007 10:17 AM writes...

You've captured exactly what makes organic chemistry fun and so different from most of the rest of science - making something new that didn't previously exist.

Here is how I try to explain organic chemistry to friends and family: It's a combination of science, engineering and art. The other sciences are observational. One perturbs a natural system and observes the result. New knowledge is generated by these efforts. Engineering uses existing scientific knowledgeto build new things. The outcome of an engineer's efforts is never in doubt, if enough money, effort and time is expended, the new chip, building, bridge, rocket, etc. can be built. The organic chemist, by contrast, creates something novel without knowing whether it is even possible. A priori, we can hypothesize about the structure's properties but unless we can actually make it, these ideas cannot be tested. We are unable to predict, with certainty, whether a particular structure can be synthesized. Once made, we are often surprised to learn that it doesn't have the expected properties. Organic chemistry generates both new knowledge and new things.

The art of organic chemistry is two-fold. 1) Some molecular structures possess an intrinsic beauty or ugliness. 2) Synthetic routes can be utilitatian (the hammer & tongs approach using well known reactions) or elegant (using new reactions, taking advantage of symmetry, avoiding protecting groups, etc.).

I think that only an organic chemist can truly understand the excitement and sense of accomplishment at seeing positive assay results for a new analog or a batch of pure crystals forming in a flask.

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2. Jose on November 15, 2007 11:07 AM writes...

Derek, you are in a very lucky place! Congrats!

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3. Another Kevin on November 15, 2007 11:31 AM writes...

Hmm, I thought that the technical term for that gooey dark stuff was Complex Residues And Products. (Although the acronym is more often heard.)

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4. Chemgeek on November 15, 2007 11:46 AM writes...

It's a cool feeling having the WORLD'S SUPPLY of compound XYZ in a flask that you are holding in your hand. Of course, there may be a bacteria living in a hot ocean vent 3 miles deep that is producing XYZ by the pound, but what do bacteria know about anything anyways.

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5. Nick K on November 15, 2007 12:37 PM writes...

An under-appreciated facet of Organic Chemistry is the fact that it is as much a craft as a science. The theoretical background is vital, of course, but we still have to work on physical materials with our hands to get reactions to work and to obtain subtantial amounts of pure compounds at the end.

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6. qetzal on November 15, 2007 12:52 PM writes...

Derek, I'm curious.

Is there a rationale for pursuing all this? I mean, other than simply the scientific and IP lures of uncharted territory. E.g, maybe there's a particular target that you think cries out for compounds in this previously ignored class?

I don't expect you to explain what the rationale is, of course, just wondering if one exists.

More generally, is there still a lot of uncharted territory like this in the med-chem biz? How common are such projects, compared to what you would consider 'routine' projects? Does pharma deliberately veer off into the wilderness on occasion, just to see if there's anything there? Or is some compelling rationale usually required?

Maybe this is worth another post.

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7. Green Koala on November 15, 2007 2:50 PM writes...

It is good to see examples of this level of excitement for organic chemistry. We're all envious.

My question is at what point is the group required to show progress towards a clinical candidate, or do you have a mandate such that this is expected to have long term downstream benefits, thus no real short term goals other than novelty. Maybe too direct a question for such a venue.

It does remind me of the excitement in getting into the field. I remember sitting in Advanced Organic my junior year in college watching as Woodward's synthesis of cholesterol was described, and thinking Wow, that's pretty cool, making an actual complex molecule God had created. And then realizing in undergrad research that I had just created something that even God hadn't. And then realizing as a med chemist that I could create novel entities that could actually help mankind!

Ahhh, the unjaded years.

Some of this ego is subconscious in all of us; we do have to have some level of confidence in our abilities to bring something novel. Just, sometimes it gets out of control or misinterpreted, leading to a reputation of arrogance. [Which I don't understand. If we chemists are always right, how can it be arrogance?].

Still fun though. Like Derek, I revel in the fact that I get to do something different everyday, no matter how much corporate noise is around me.

(still scared of inflatable iguanas)

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8. Derek Lowe on November 15, 2007 3:04 PM writes...

The rationale is sort of general - these are classes of compounds that I'd expect to have quite different properties than the other things we have in our screening files. I don't have a single target in mind (yet). We'd want to take a look and see what these various things are like from a med-chem standpoint once they're made, which might involve picking some structures that we already know a lot about that these new things might be close analogs of, and seeing what happens to them.

And yeah, I'd say that overall this sort of thing is fairly uncommon. I think a few of the larger companies devote a bit of time to it, though.

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9. Anonymous BMS Researcher on November 15, 2007 10:25 PM writes...

Almost ANY oddball molecule, unless it is clearly not "druglike," can at least end up in a screening deck...

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