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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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September 19, 2007

The Good Old CombiChem Days

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Posted by Derek

Yesterday's post set off a discussion of the 1990s combichem boom in the comments. I joined the industry before that took off, and watched it with interest.

For those outside the field, combinatorial chemistry was (is, I guess) the semi-automated generation of large numbers of diverse organic compounds. The basic idea was that you'd start with, say, building block A, which would react with a big library of reactant partners B1. . .Bzillion. The resulting compounds would then be reacted with another big set of coupling partners, C1. . .Cmonstrous, and this might be designed to take place out at the end of the B part, or on another part of the A region, etc. There were many pool-split-mix methods worked out to generate the maximum number of different compounds. Various strategies generated either individual compounds or mixtures of different ones and all sorts of techniques were developed to make it all happen in a less labor-intensive fashion. These included bonding the starting materials (or the reagents) onto solid resin bead supports until the end of the synthesis, the better to move things around, along with ingenious schemes for tagging and identifying what was ending up in which vials.

The idea was that we'd generate lots (lots) more compounds for random screening than we'd ever have before. And for a while, it looked like the companies that did this the first with the most were going to have the drop on everyone else. It stood to reason - many of our high-throughput screens didn't generate anything useful to start working on, so if technology now allowed you to brute-force your way into getting things to hit, well, you'd be crazy not to.

A frenzy ensued. People that no one had heard of were suddenly in demand as consultants and invited speakers at conferences. Whole companies were started to make and sell combinatorial libraries of compounds - a couple of them are even still in business, although the road has been pretty jumpy. Larger companies started in-house efforts, some of them rather lavish. Some people talked about traditional medicinal chemistry receding to a specialty, as the mighty compound factories came on line (more than one person tried to sell me on this idea personally).

But as time went on, and the piles of combichem stuff made it into the screening collections, people began to note with unease that, well, not so many lead compounds were coming out. In fact, it eventually became clear that the hit rate for most combichem stuff was lower than for the general old-fashioned screening collections. That went double for the combi libraries from the first part of the boom, many of which are now regarded as basically worthless.

What happened? Well, the techniques that generated larger mixtures of compounds were trouble from the start, because it's hard enough to screen individual compounds well. But even single-compound collections had their problems. A larger difficulty was that the chemistry that could be used under the more highly automated combichem protocols was limited. Many useful reactions were bypassed because there was no good way to do them on solid supports with minimal purification afterwards. There sure were an awful lot of amides, ureas, and sulfonamides produced, I can tell you. Not that there's anything wrong with these groups, but when you start to have multiple instances of them in the same molecule, you can veer off into undesirable territory.

Overall, as has been realized, the chemical diversity offered by combichem's early years was largely spurious. People went out and did the stuff that was easiest to do, with what was on hand, and that translated to a much spottier coverage of chemical space than was first realized. Combichem itself survives, but compared to the mid-1990s it's a backwater.

But there's still a place for it. People have been steadily introducing a greater variety of chemistry into it, and everyone's now more aware of how hard it is to make truly diverse compound collections. Once the hot air hissed out of it, combichem was revealed as what it really had been all along: a tool. One of many, to be used as appropriate.

Update: Here's a take on the field from the inside, from Org Prep Daily.

Comments (10) + TrackBacks (0) | Category: Drug Industry History


COMMENTS

1. Rich Apodaca on September 19, 2007 10:07 AM writes...

As the saying goes, when all you have is a hammer, everything else is a nail...

It's perplexing to see chemists continue to do large matrix synthesis when their SAR is clearly additive or too flat (5-fold difference is barely meaningful in many assays). Seeing results like that, I don't need to make every combination - it's actually a _lot_ slower and more resource-wasting to work that way.

Depending on how late you are in your program, the biology half of the team may not even be capable of handling all of the compounds being made; making more of them does nothing to move the project forward.

If I see non-additive in vitro SAR (trends across rows and columns don't match), then I start to think about large matrix synthesis. But the instances of non-additive SAR in the projects I worked on were remarkably rare.

Half the battle is finding the right tool for the job.

Permalink to Comment

2. Not A Chemist on September 19, 2007 11:54 AM writes...

So at my drug factory I hear groups talking about (or even calling themselves) Parallel Medicinal Chemistry. Is that an oxymoron or what combichem has morphed into?

Permalink to Comment

3. Jose on September 19, 2007 12:04 PM writes...

I *do* miss the productivity numbers from those days though; 192 compounds most weeks, for an annual total of ~7000? These days I am lucky to get 2-3 targets a month! The S/N appears to be inversely correlated though....

Permalink to Comment

4. Petros on September 19, 2007 1:59 PM writes...

Some of us predate that

1 to 2 months for a well designed compound, with a few mg purified by HPLC!

And I remmeber the garbage taht went into the initial WDF screening collections.

We were able to select compounds from the Agrochem guy's output.

Their registray card's had a box for purity which sometimes had values of 20% or lower!

Permalink to Comment

5. paiute on September 19, 2007 2:48 PM writes...

Yeah, but it let you claim that instead of a tarry failure, your reaction had generated a library.

Permalink to Comment

6. Bacon on September 19, 2007 3:27 PM writes...

Disclaimer: I'm an academic chemist.

I never understood all the anti-combichem sentiments.* I agree that it isn't a cure all or solution for every problem (and I'm glad to hear you not claiming it a failure, Derek).

One question I have... what is the common timeframe for development of a drug? You often hear CombiChem being harped on in that it didn't provide any drug products, however, that tide might be changing (see Januvia and others). It's been probably 15 years since the hype of combichem, is it that crazy that drugs are just now coming to market from these efforts?

* = I do understand some anger with the hype, when certain academics claimed they would have a compound for every known target using Diversity Oriented Synthesis by the year 2000. But in my opinion, DOS is not true CombiChem (directed libraries). Maybe the muddling of the two causes CombiChem to come off in a negative manner?

Permalink to Comment

7. bitter pill on September 19, 2007 6:20 PM writes...

re; 6

I think a lot of the anger at combichem was from those of us asked to "follow up" on some of the lousy compounds from combichem in the intial wave. Having to justify why you won't follow up on an alkyl halide tends to make one less than happy with the hype. Also, watching the combichem guys shrug when deconvolution of their library yielded none of the claimed stuctures did not help. Of course they had already been promoted for their "contributions"

Permalink to Comment

8. milkshake on September 19, 2007 6:35 PM writes...

Shamelessly self-promoting plug: I was going to post a comple comments, about my years in combichem - but it would be too long. I wrote a new post about combichem, in Org Prep Daily

Permalink to Comment

9. Polymer Bound on September 19, 2007 7:50 PM writes...

"So at my drug factory I hear groups talking about (or even calling themselves) Parallel Medicinal Chemistry. Is that an oxymoron or what combichem has morphed into?"

Kinda... except the compounds are probably getting purified in a high throughput fashion and the libraries are much smaller (

Permalink to Comment

10. Anonymous on September 19, 2007 9:35 PM writes...

Here's a nice 2002 paper comparing the chemical diverstiy of combichem, naturally-found chemicals, and existing drugs. Guess which class has the lower diversity?

http://pubs.acs.org/cgi-bin/sample.cgi/jcisd8/2003/43/i01/pdf/ci0200467.pdf

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